Heterocyclic metalloprotease inhibitors

ABSTRACT

The invention provides compounds of formula  
                 
 
     as described in the claims, or an optical isomer, diastereomer or enantiomer thereof, or a pharmaceutically-acceptable salt, or biohydrolyzable amide, ester, or imide thereof are useful as inhibitors of metalloproteases.  
     Also disclosed are pharmaceutical compositions and methods of treating diseases, disorders and conditions characterized by metalloprotease activity using these compounds or the pharmaceutical compositions containing them.

CROSS REFERENCE

[0001] This application claims priority under Title 35, United StatesCode 119(e) from Provisional Application Serial No. 60/024,764, filedAug. 28, 1996.

TECHNICAL FIELD

[0002] This invention is directed to compounds which are useful intreating diseases, disorders and conditions associated with unwantedmetalloprotease activity.

BACKGROUND

[0003] A number of structurally related metalloproteases [MPs] effectthe breakdown of structural proteins. These metalloproteases often acton the intercellular matrix, and thus are involved in tissue breakdownand remodeling. Such proteins are referred to as metalloproteases orMPs. There are several different families of MPs, classified by sequencehomology. Several families of known MPs, as well as examples thereof,are disclosed in the art.

[0004] These MPs include Matrix-Metallo Proteases [MMPS], zincmetalloproteases, many of the membrane bound metalloproteases, TNFconverting enzymes, angiotensin-converting enzymes (ACEs), disintegrins,including ADAMs (See Wolfsberg et al, 131 J. Cell Bio. 275-78 October,1995), and the enkephalinases. Examples of MPs include human skinfibroblast collagenase, human skin fibroblast gelatinase, human sputumcollagenase, aggrecanse and gelatinase, and human stromelysin.Collagenase, stromelysin, aggrecanase and related enzymes are thought tobe important in mediating the symptomatology of a number of diseases.

[0005] Potential therapeutic indications of MP inhibitors have beendiscussed in the literature. See for example, U.S. Pat. No. 5,506,242(Ciba Geigy Corp.); U.S. Pat. No. 5.403,952 (Merck & Co.); PCT publishedapplication WO 96/06074 (British Bio Tech Ltd); PCT Publication WO96/00214 (Ciba Geigy); WO 95/35275 (British Bio Tech Ltd); WO 95/35276(British Bio Tech Ltd); WO 95/33731 (Hoffman-LaRoche); WO 95/33709(Hoffman-LaRoche); WO 95/32944 (British Bio Tech Ltd); WO 95/26989(Merck); WO 9529892 (DuPont Merck); WO 95/24921 (Inst. Opthamology); WO95/23790 (SmithKline Beecham); WO 95/22966 (Sanofi Winthrop); WO95/19965 (Glycomed); WO 95 19956 (British Bio Tech Ltd); WO 95/19957(British Bio Tech Ltd); WO 95/19961 (British Bio Tech Ltd) WO 95/13289(Chiroscience Ltd.); WO 95/12603 (Syntex); WO 95/09633 (Florida StateUniv); WO 95/09620 (Florida State Univ.); WO 95/04033 (Celltech); WO94/25434 (Celltech); WO 94/25435 (Celltech); WO 93/14112 (Merck); WO94/0019 (Glaxo); WO 93/21942 (British Bio Tech Ltd); WO 92/22523 (Res.Corp. Tech. Inc.); WO 94/10990 (British Bio (Yamanouchi); and Britishpatents GB 2282598 (Merck) and GB 2268934 (British Bio Tech Ltd);Published European Patent Applications EP 95/684240 (Hoffman LaRoche);EP 574758 (Hoffman LaRoche); EP 575844 (Hoffman LaRoche); PublishedJapanese applications; JP 08053403 (Fujusowa Pharm. Co. Ltd.); JP7304770 (Kanebo Ltd.); and Bird et al J. Med Chem vol. 37, pp. 158-69(1994). Examples of potential therapeutic uses of MP inhibitors includerheumatoid arthritis (Mullins, D. E., et al., Biochim. Biophys. Acta.(1983) 695:117-214); osteoarthritis (Henderson, B., et al., Drugs of theFuture (1990) 15:495-508); the metastasis of tumor cells (ibid,Broadhurst, M. J., et al., European Patent Application 276,436(published 1987), Reich, R., et al., 48 Cancer Res. 3307-3312 (1988);and various ulcerations or ulcerative conditions of tissue. For example,ulcerative conditions can result in the cornea as the result of alkaliburns or as a result of infection by Pseudomonas aeruginosa,Acanthamoeba, Herpes simplex and vaccinia viruses.

[0006] Other examples of conditions characterized by undesiredmetalloprotease activity include periodontal disease, epidermolysisbullosa, fever, inflammation and scleritis (Cf. DeCicco et al, WO 9529892 published Nov. 9, 1995).

[0007] In view of the involvement of such metalloproteases in a numberof disease conditions, attempts have been made to prepare inhibitors tothese enzymes. A number of such inhibitors are disclosed in theliterature. Examples include U.S. Pat. No. 5,183,900, issued Feb. 2,1993 to Galardy; U.S. Pat. No. 4,996,358, issued Feb. 26, 1991 to Handa,et al.; U.S. Pat. No. 4,771,038, issued Sep. 13, 1988 to Wolanin, etal.; U.S. Pat. No. 4,743,587, issued May 10, 1988 to Dickens, et al.,European Patent Publication Number 575,844, published Dec. 29, 1993 byBroadhurst, et al.; International Patent Publication No. WO 93/09090,published May 13, 1993 by Isomura, et al.; World Patent Publication92/17460, published Oct. 15, 1992 by Markwell et al.; and EuropeanPatent Publication Number 498,665, published Aug. 12, 1992 by Beckett,et al.

[0008] Metalloprotease inhibitors are useful in treating diseasescaused, at least in part, by breakdown of structural proteins. Though avariety of inhibitors have been prepared, there is a continuing need forpotent matrix metalloprotease inhibitors useful in treating suchdiseases. Applicants have found that, surprisingly, the compounds of thepresent invention are potent metalloprotease inhibitors.

OBJECTS OF THE INVENTION

[0009] Thus it is an object of the present invention to providecompounds useful for the treatment of conditions and diseases which arecharacterized by unwanted MP activity.

[0010] It is also an object of the invention to provide potentinhibitors of metalloproteases.

[0011] It is a further object of the invention to provide pharmaceuticalcompositions comprising such inhibitors.

[0012] It is also an object of the invention to provide a method oftreatment for metalloprotease related maladies.

SUMMARY OF THE INVENTION

[0013] The invention provides compounds which are useful as inhibitorsof metalloproteases, and which are effective in treating conditionscharacterized by excess activity of these enzymes. In particular, thepresent invention relates to a compound having a structure according toFormula (I)

[0014] wherein

[0015] R₁ is H;

[0016] R₂ is hydrogen, alkyl or acyl;

[0017] Ar is COR₃ or S₂R₄; and

[0018] R₃ is alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl,heteroalkyl, amino, alkylamino, dialkylamino, arylamino andalkylarylamino;

[0019] R₄ is alkyl, heteroalkyl, aryl, or heteroaryl, substituted orunsubstituted;

[0020] X is CH₂, O, S, SO, SO₂, or NR₅, wherein R₅ is independentlychosen from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, SO₂R₆, COR₇,CSR₈, PO(R₉)₂ or may optionally form a ring with W; and

[0021] R₆ is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino,dialkylamino, arylamino, diarylamino and alkylarylamino;

[0022] R₇ is hydrogen, alkoxy, aryloxy, heteroaryloxy, alkyl, aryl,heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino andalkylarylamino;

[0023] R₈ is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino,dialkylamino, arylamino, diarylamino and alkylarylamino;

[0024] R₉ is alkyl, aryl, heteroaryl, heteroalkyl;

[0025] W is hydrogen or one or more lower alkyl moieties, or is analkylene, arylene, or heteroarylene bridge between two adjacent ornonadjacent carbons (thus forming a fused ring);

[0026] Y is independently one or more of hydrogen, hydroxy, SR₁₀, SOR₄,SO₂R₄, alkoxy, amino, wherein amino is of formula NR₁₁,R₁₂, wherein R₁₁and R₁₂ are independently chosen from hydrogen, alkyl, heteroalkyl,heteroaryl, aryl, SO₂R₆, COR₇, CSR₈, PO(R₉)₂; and

[0027] R₁₀ is hydrogen, alkyl, aryl, heteroaryl;

[0028] Z is nil, a spiro moiety or an oxo group substituted on theheterocyclic ring;

[0029] n is 1-3.

[0030] This structure also includes an optical isomer, diastereomer orenantiomer for Formula (I), or a pharmaceutically-acceptable salt, orbiohydrolyzable amide, ester, or imide thereof.

[0031] These compounds have the ability to inhibit at least onemammalian metalloprotease. Accordingly, in other aspects, the inventionis directed to pharmaceutical compositions containing the compounds ofFormula (I), and to methods of treating diseases characterized byunwanted metalloprotease activity using these compounds or thepharmaceutical compositions containing them.

[0032] Metalloproteases which are active at a particularly undesiredlocation (e.g., an organ or certain types of cells) can be targeted byconjugating the compounds of the invention to a targeting ligandspecific for a marker at that location such as an antibody or fragmentthereof or a receptor ligand. Conjugation methods are known in the art.

[0033] The invention is also directed to various other processes whichtake advantage of the unique properties of these compounds. Thus, inanother aspect, the invention is directed to the compounds of Formula(I) conjugated to solid supports. These conjugates can be used asaffinity reagents for the purification of a desired metalloprotease.

[0034] In another aspect, the invention is directed to the compounds ofFormula (I) conjugated to label. As the compounds of the invention bindto at least one metalloprotease, the label can be used to detect thepresence of relatively high levels of metalloprotease, preferably amatrix metalloprotease in vivo or in vitro cell culture.

[0035] In addition, the compounds of Formula (I) can be conjugated tocarriers which permit the use of these compounds in immunizationprotocols to prepare antibodies specifically immunoreactive with thecompounds of the invention. Typical conjugation methods are known in theart. These antibodies are then useful both in therapy and in monitoringthe dosage of the inhibitors.

DETAILED DESCRIPTION

[0036] The compounds of the present invention are inhibitors ofmammalian metalloproteases, preferably a matrix metalloproteases.Preferably, the compounds are those of Formula (I) or apharmaceutically-acceptable salt, or biohydrolyzable amide, ester, orimide thereof.

[0037] Throughout this disclosure, publications and patents are referredto in an effort to fully describe the state of the art. All referencescited herein are hereby incorporated by reference.

[0038] Definitions and Usage of Terms:

[0039] The following is a list of definitions for terms used herein.

[0040] “Acyl” or “carbonyl” is described as a radical which could beformed by removal of the hydroxy from a carboxylic acid (i.e.,R—C(═O)—). Preferred acyl groups include (for example) acetyl, formyl,and propionyl.

[0041] “Acyloxy” is an oxy radical having an acyl substituent (i.e.,—O-acyl); for example, —O—C(═O)-alkyl.

[0042] “Alkoxyacyl” is an acyl radical (—C(═O)—) having an alkoxysubstituent (i.e., —O—R), for example, —C(═O)—O-alkyl. This radical canbe referred to as an ester.

[0043] “Acylamino” is an amino radical having an acyl substituent (i.e.,—N-acyl); for example, —NH—C(═O)-alkyl.

[0044] “Alkenyl” is an unsubstituted or substituted hydrocarbon chainradical having 2 to 15 carbon atoms; preferably from 2 to 10 carbonatoms; more preferably from 2 to 8; except where indicated. Alkenylsubstituents have at least one olefinic double bond (including, forexample, vinyl, allyl and butenyl).

[0045] “Alkynyl” is an unsubstituted or substituted hydrocarbon chainradical having 2 to 15 carbon atoms; preferably from 2 to 10 carbonatoms; more preferably from 2 to 8; except where indicated. The chainhas at least one carbon-carbon triple bond.

[0046] “Alkoxy” is an oxygen radical having a hydrocarbon chainsubstituent, where the hydrocarbon chain is an alkyl or alkenyl (i.e.,—O-alkyl or —O-alkenyl). Preferred alkoxy groups include (for example)methoxy, ethoxy, propoxy and allyloxy.

[0047] “Alkoxyalkyl” is an unsubstituted or substituted alkyl moietysubstituted with an alkoxy moiety (i.e., -alkyl-O-alkyl). Preferred iswhere the alkyl has 1 to 6 carbon atoms (more preferably 1 to 3 carbonatoms), and the alkyoxy has 1 to 6 carbon atoms (more preferably 1 to 3carbon atoms).

[0048] “Alkyl” is an unsubstituted or substituted saturated hydrocarbonchain radical having 1 to 15 carbon atoms; preferably from 1 to 10carbon atoms; more preferably 1 to 4; except where indicated. Preferredalkyl groups include (for example) substituted or unsubstituted methyl,ethyl, propyl, isopropyl, and butyl.

[0049] As referred to herein, “spiro cycle” or “spiro cyclic” refers toa cyclic moiety sharing a carbon on another ring. Such cyclic moiety maybe carbocyclic or heterocyclic in nature. Preferred heteroatoms includedin the backbone of the heterocyclic spirocycle include oxygen, nitrogenand sulfur. The spiro cycles may be unsubstituted or substituted.Preferred substituents include oxo, hydroxy, alkyl, cycloalkyl,arylalkyl, alkoxy, amino, heteroalkyl, aryloxy, fused rings (e.g.,benzothiole, cycloalkyl, heterocycloalkyl, benzimidizoles,pyridylthiole, etc., which may also be substituted) and the like. Inaddition, the heteroatom of the heterocycle may be substituted ifvalence allows. Preferred spirocyclic ring sizes include 3-7 memberedrings.

[0050] Alkylene refers to an alkyl, alkenyl or alkynyl which isdiradical, rather than a radical. “Hetero alkylene” is likewise definedas a (diradical) alkylene having a heteroatom in its chain.

[0051] “Alkylamino” is an amino radical having one (secondary amine) ortwo (tertiary amine) alkyl substituents (i.e., —N-alkyl). For example,methylamino (—NHCH₃), dimethylamino (—N(CH₃)₂), methylethylamino(—N(CH₃)CH₂CH₃).

[0052] “Aminoacyl” is acyl radical having an amino substituent (i.e.,—C(═O)—N); for example, —C(═O)—NH₂. The amino group of the aminoacylmoiety may be unsubstituted (i.e., primary amine) or may be substitutedwith one (secondary amine) or two (i.e., tertiary amine) alkyl groups.

[0053] “Aryl” is an aromatic carbocyclic ring radical. Preferred arylgroups include (for example) phenyl, tolyl, xylyl, cumenyl, naphthyl,biphenyl and fluorenyl. Such groups may be substituted or unsubstituted.

[0054] “Arylalkyl” is an alkyl radical substituted with an aryl group.Preferred arylalkyl groups include benzyl, phenylethyl, andphenylpropyl. Such groups may be substituted or unsubstituted.“Arylalkylamino” is an amine radical substituted with an arylalkyl group(e.g., —NH-benzyl). Such groups may be substituted or unsubstituted.

[0055] “Arylamino” is an amine radical substituted with an aryl group(i.e., —NH-aryl). Such groups may be substituted or unsubstituted.

[0056] “Aryloxy” is an oxygen radical having an aryl substituent (i.e.,—O-aryl). Such groups may be substituted or unsubstituted.

[0057] “Carbocyclic ring” is an unsubstituted or substituted, saturated,unsaturated or aromatic, hydrocarbon ring radical. Carbocyclic rings aremonocyclic or are fused, bridged or spiro polycyclic ring systems.Monocyclic carbocyclic rings generally contain 4 to 9 atoms, preferably4 to 7 atoms. Polycyclic carbocyclic rings contain 7 to 17 atoms,preferably from 7 to 12 atoms. Preferred polycyclic systems comprise 4-,5-, 6- or 7-membered rings fused to 5-, 6-, or 7-membered rings.

[0058] “Carbocycle-alkyl” is an unsubstituted or substituted alkylradical substituted with a carbocyclic ring. Unless otherwise specified,the carbocyclic ring is preferably an aryl or cycloalkyl; morepreferably an aryl Preferred carbocycle-alkyl groups include benzyl,phenylethyl and phenylpropyl.

[0059] “Carbocycle-heteroalkyl” is an unsubstituted or substitutedheteroalkyl radical substituted with a carbocyclic ring. Unlessotherwise specified, the carbocyclic ring is preferably an aryl orcycloalkyl; more preferably an aryl. The heteroalkyl is preferably2-oxa-propyl, 2-oxa-ethyl, 2-thia-propyl, or 2-thia-ethyl.

[0060] “Carboxyalkyl” is an unsubstituted or substituted alkyl radicalsubstituted with a carboxy (—C(═O)OH) moiety. For example, —CH₂—C(═O)OH.

[0061] “Cycloalkyl” is a saturated carbocyclic ring radical. Preferredcycloalkyl groups include (for example) cyclopropyl, cyclobutyl andcyclohexyl.

[0062] “Cycloheteroalkyl” is a saturated heterocyclic ring. Preferredcycloheteroalkyl groups include (for example) morpholinyl, piperadinyl,piperazinyl, tetrahydrofuryl and hydantoinyl.

[0063] “Fused rings” are rings that are superimposed together such thatthey share two ring atoms. A given ring may be fused to more than oneother ring. Fused rings are contemplated in heteroaryl, aryl andheterocycle radicals or the like.

[0064] “Heterocycle-alkyl” is an alkyl radical substituted with aheterocyclic ring. The heterocyclic ring is preferably a heteroaryl orcycloheteroalkyl; more preferably a heteroaryl. Preferred heterocyclealkyl include C₁-C₄ alkyl having preferred heteroaryl appended to them.More preferred is, for example, pyridyl alkyl, and the like.

[0065] “Heterocycle-heteroalkyl” is an unsubstituted or substitutedheteroalkyl radical substituted with a heterocyclic ring. Theheterocyclic ring is preferably an aryl or cycloheteroalkyl; morepreferably an aryl.

[0066] “Heteroatom” is a nitrogen, sulfur or oxygen atom. Groupscontaining one or more heteroatoms may contain different heteroatoms.

[0067] “Heteroalkenyl” is an unsubstituted or substituted unsaturatedchain radical having 3 to 8 members comprising carbon atoms and one ortwo heteroatoms. The chain has at least one carbon-carbon double bond.

[0068] “Heteroalkyl” is an unsubstituted or substituted saturated chainradical having 2 to 8 members comprising carbon atoms and one or twoheteroatoms.

[0069] “Heterocyclic ring” is an unsubstituted or substituted,saturated, unsaturated or aromatic ring radical comprised of carbonatoms and one or more heteroatoms in the ring. Heterocyclic rings aremonocyclic or are fused, bridged or spiro polycyclic ring systems.Monocyclic heterocyclic rings contain 3 to 9 atoms, preferably 4 to 7atoms. Polycyclic rings contain 7 to 17 atoms, preferably from 7 to 13atoms.

[0070] “Heteroaryl” is an aromatic heterocyclic ring, either monocyclicor bicyclic radical. Preferred heteroaryl groups include (for example)thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl,quinolinyl, and tetrazolyl, benzo thiazolyl, benzofuryl, indolyl and thelike. Such groups may be substituted or unsubstituted.

[0071] “Halo”, “halogen”, or “halide” is a chloro, bromo, fluoro or iodoatom radical. Bromo, chloro and fluoro are preferred halides.

[0072] Also, as referred to herein, a “lower” hydrocarbon moiety (e.g.,“lower” alkyl) is a hydrocarbon chain comprised of 1 to 6, preferablyfrom 1 to 4, carbon atoms.

[0073] A “pharmaceutically-acceptable salt” is a cationic salt formed atany acidic (e.g., carboxyl) group, or an anionic salt formed at anybasic (e.g., amino) group. Many such salts are known in the art, asdescribed in World Patent Publication 87/05297, Johnston et al.,published Sep. 11, 1987 (incorporated by reference herein). Preferredcationic salts include the alkali metal salts (such as sodium andpotassium), and alkaline earth metal salts (such as magnesium andcalcium) and organic salts. Preferred anionic salts include the halides(such as chloride salts).

[0074] “Biohydrolyzable amides” are amides of the compounds of theinvention that do not interfere with the inhibitory activity of thecompound, or that are readily converted in vivo by a mammal subject toyield an active inhibitor.

[0075] A “biohydrolyzable hydroxy imide” is an imide of a Formula (I)compound that does not interfere with the metalloprotease inhibitoryactivity of these compounds, or that is readily converted in vivo by amammal subject to yield an active Formula (I) compound. Such hydroxyimides include those that do not interfere with the biological activityof the Formula (I) compounds.

[0076] A “biohydrolyzable ester” refers to an ester of a Formula (I)compound that does not interfere with the metalloprotease inhibitoryactivity of these compounds or that is readily converted by an animal toyield an active Formula (I) compound.

[0077] A “solvate” is a complex formed by the combination of a solute(e.g., a metalloprotease inhibitor) and a solvent (e.g., water). See J.Honig et al., The Van Nostrand Chemist's Dictionary, p. 650 (1953).Pharmaceutically-acceptable solvents used according to this inventioninclude those that do not interfere with the biological activity of themetalloprotease inhibitor (e.g., water, ethanol, acetic acid,N,N-dimethylformamide and others known or readily determined by theskilled artisan).

[0078] “Optical isomer”, “stereoisomer”, “diastereomer” as referred toherein have the standard art recognized meanings (Cf., Hawley'sCondensed Chemical Dictionary, 11th Ed.).

[0079] The illustration of specific protected forms and otherderivatives of the Formula (I) compounds is not intended to be limiting.The application of other useful protecting groups, salt forms, etc. iswithin the ability of the skilled artisan.

[0080] As defined above and as used herein, substituent groups maythemselves be substituted. Such substitution may be with one or moresubstituents. Such substituents include those listed in C. Hansch and A.Leo, Substituent Constants for Correlation Analysis in Chemistry andBiology (1979), incorporated by reference herein. Preferred substituentsinclude (for example) alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro,amino, aminoalkyl (e.g., aminomethyl, etc.), cyano, halo, carboxy,alkoxyaceyl (e.g., carboethoxy, etc.), thiol, aryl, cycloalkyl,heteroaryl, heterocycloalkyl (e.g., piperidinyl, morpholinyl,pyrrolidinyl, etc.), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl,and combinations thereof.

[0081] As used herein, “mammalian metalloprotease” means anymetal-containing enzyme found in mammalian sources which is capable ofcatalyzing the breakdown of collagen, gelatin or proteoglycan undersuitable assay conditions. Appropriate assay conditions can be found,for example, in U.S. Pat. No. 4,743,587, which references the procedureof Cawston, et al., Anal. Biochem. (1979) 99:340-345, use of a syntheticsubstrate is described by Weingarten, H., et al., Biochem. Biophy. Res.Comm. (1984) 139:1184-1187. Any standard method for analyzing thebreakdown of these structural proteins can, of course, be used. Themetalloprotease enzymes referred to herein are all zinc-containingproteases which are similar in structure to, for example, humanstromelysin or skin fibroblast collagenase. The ability of candidatecompounds to inhibit metalloprotease activity can, of course, be testedin the assays described above. Isolated metalloprotease enzymes can beused to confirm the inhibiting activity of the invention compounds, orcrude extracts which contain the range of enzymes capable of tissuebreakdown can be used.

[0082] Compounds:

[0083] Compounds of the invention are described in the Summary of theInvention. Preferred compounds of the invention are those in which Z isheterospiroalkylene, preferably having heteroatoms adjacent to theparent ring structure, more preferably such spiroheteroalkylenes have 4to 5 members. Preferred heteroatoms are divalent.

[0084] The invention provides compounds which are useful as inhibitorsof metalloproteases, preferably a matrix metalloproteases, and which areeffective in treating conditions characterized by excess activity ofthese enzymes. In particular, the present invention relates to acompound having a structure according to Formula (I)

[0085] wherein

[0086] R₁ is H;

[0087] R₂ is hydrogen, alkyl or acyl;

[0088] Ar is COR₃ or SO₂R₄; and

[0089] R₃ is alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl,heteroalkyl, amino, alkylamino, dialkylamino, arylamino andalkylarylamino;

[0090] R₄ is alkyl, heteroalkyl, aryl, or heteroaryl, substituted orunsubstituted;

[0091] X is CH₂, O, S, SO, SO₂, or NR₅, wherein R₅ is independentlychosen from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, SO₂R₆, COR₇,CSR₈, PO(R₉)₂ or may optionally form a ring with W; and

[0092] R₆ is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino,dialkylamino, arylamino, diarylamino and alkylarylamino;

[0093] R₇ is hydrogen, alkoxy, aryloxy, heteroaryloxy, alkyl, aryl,heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino andalkylarylamino;

[0094] R₈ is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino,dialkylamino, arylamino, diarylamino and alkylarylamino;

[0095] R₉ is alkyl, aryl, heteroaryl, heteroalkyl;

[0096] W is hydrogen or one or more lower alkyl moieties, or is analkylene, arylene, or heteroarylene bridge between two adjacent ornonadjacent carbons (thus forming a fused ring);

[0097] Y is independently one or more of hydrogen, hydroxy, SR₁₀, SOR₄,SO₂R₄, alkoxy, amino, wherein amino is of formula NR₁₁,R₁₂, wherein R₁₁and R₁₂ are independently chosen from hydrogen, alkyl, heteroalkyl,heteroaryl, aryl, SO₂R₆, COR₇, CSR₈, PO(R₉)₂; and

[0098] R₁₀ is hydrogen, alkyl, aryl, heteroaryl;

[0099] Z is nil, a spiro moiety or an oxo group substituted on theheterocyclic ring;

[0100] n is 1-3.

[0101] This structure also includes an optical isomer, diastereomer orenantiomer for Formula (I), or a pharmaceutically-acceptable salt, orbiohydrolyzable ester, amide, or imide thereof.

[0102] Compound Preparation:

[0103] The hydroxamic compounds of Formula (I) can be prepared using avariety of procedures. General schemes include the following.

[0104] PREPARATION OF THE Y MOIETY

[0105] For the manipulation of Y it is understood that the skilledartisan may choose to prepare Y before, after or concurrent with thepreparation of the heterocyclic ring. For clarity, the W and Z moietyare not shown below. More than one Y and Z may be present in thecompounds of formula (I). For compounds where Y is not adjacent to thering nitrogen, a preferred method of making the compounds is;

[0106] Where R is a derivatizable group or can be manipulated orsubstituted, such compounds are known or are prepared by known methods.(A) is converted to its analogous sultamester and R is manipulated togive (B) during this or a subsequent step. Y and Z can be added oraltered, followed by appropriate reaction to provide R₁. For example,this step may include treatment with hydroxyl amine under basicconditions to give a compound of formula I (C).

[0107] For the preparation and elaboration of the heterocyclic ring itis understood that the skilled artisan may choose to prepare Y before,after or concurrent with the preparation of the heterocyclic ring. Forclarity, the W, Y, and Z moiety are not shown below. More than one W, Yand Z may be present in the compounds of formula (I). For compoundswhere X is nitrogen, the preferred method for the manipulation of R₅ isshown. In the scheme below, L is any acceptable leaving group, and B isa blocking group as above, Boc is an example of a preferred, and artrecognized blocking group. The skilled artisan will recognize that thechoice of blocking group is within the skill of the artisan working inorganic chemistry. Thus the choice of Boc is not required, butpreferred.

[0108] For compounds containing a sulfur in the heterocyclic ring thepreferred methods of ring formation are shown. For the preparation andelaboration of the heterocyclic ring it is understood that the skilledartisan may choose to prepare Y before, after or concurrent with thepreparation of the heterocyclic ring. For clarity, the W, Y, and Zmoiety are not shown below. More than one W, Y and Z may be present inthe compounds of formula (I).

[0109] Another acceptable strategy for making the invention having X assulfur includes the following scheme. The method allows for formation ofthe sultamester and subsequent reaction with a bifunctional moiety.Preferably the OH described in the scheme below is a primary hydroxyl.Closure of the ring uses standard methods. Functionalization andelaboration of the molecule proceeds as described above.

[0110] Where X is sulfur, further elaboration of the heterocyclic ringcan be accomplished after the ring has been formed. For example,oxidation of the ring sulfur atom using known methods can provide thecorresponding sulfoxides and sulfones as shown.

[0111] For compounds containing an oxygen in the heterocyclic ring thepreferred methods of ring formation are shown. A bifunctional moiety,for example a halo hydroxy species is reacted with an aziridine as shownbelow. The halo moiety serves as a leaving group, useful in the ringclosure reactions. Upon formation of the ring, elaboration of theinvention proceeds as described above.

[0112] Preparation of the Z Moiety

[0113] Of course the skilled artisan will recognize that schemesapplicable to the preparation of Y may be useful in the preparation of Zas noted above. Other preferred methods are provided for the reader.

[0114] Where Z is a ketal or thioketal the compounds of the inventionmay be prepared from a compound having a carbonyl in the ring. Suchcompounds are prepared by known methods, and many of such compounds areknown or commercially available. Thus the skilled artisan willappreciate that a hydroxy, amino, imino, alkoxy, oxo or any other groupthat may be manipulated into a carbonyl compound. The order ofelaborating the ketal, R₁ or the sultamester may be changed.

[0115] A preferred method of making the spiro compounds of the inventionis via a carbonyl compound, using “protecting group” technology known inthe art, such as a thioketal or ketal, and the like. Ketals, acetals andthe like are prepared from carbonyl compounds by methods known in theart. Such carbonyl compounds can be made of cyclic hydroxy alkyleneamines via oxidation to a ketone, or of lactams, which provide for2-amino spiro functionality.

[0116] A variety of compounds can be generated in a similar fashion,using the guidance of the scheme above.

[0117] In the above schemes, where R′ is alkoxy or alkylthio, thecorresponding hydroxy or thiol compounds are derived from the finalcompounds by using a standard dealkylating procedure (Bhatt, et al.,“Cleavage of Ethers”, Synthesis, 1983, pp. 249-281).

[0118] These steps may be varied to increase yield of desired product.The skilled artisan will also recognize the judicious choice ofreactants, solvents, and temperatures is an important component insuccessful synthesis. While the determination of optimal conditions,etc. is routine, it will be understood that to make a variety ofcompounds can be generated in a similar fashion, using the guidance ofthe scheme above.

[0119] The starting materials used in preparing the compounds of theinvention are known, made by known methods, or are commerciallyavailable as a starting material.

[0120] It is recognized that the skilled artisan in the art of organicchemistry can readily carry out standard manipulations of organiccompounds without further direction; that is, it is well within thescope and practice of the skilled artisan to carry out suchmanipulations. These include, but are not limited to, reduction ofcarbonyl compounds to their corresponding alcohols, oxidations ofhydroxyls and the like, acylations, aromatic substitutions, bothelectrophilic and nucleophilic, etherifications, esterification andsaponification and the like. Examples of these manipulations arediscussed in standard texts such as March, Advanced Organic Chemistry(Wiley), Carey and Sundberg, Advanced Organic Chemistry (Vol. 2) andKeeting, Heterocyclic Chemistry (all 17 volumes).

[0121] The skilled artisan will readily appreciate that certainreactions are best carried out when other functionality is masked orprotected in the molecule, thus avoiding any undesirable side reactionsand/or increasing the yield of the reaction. Often the skilled artisanutilizes protecting groups to accomplish such increased yields or toavoid the undesired reactions. These reactions are found in theliterature and are also well within the scope of the skilled artisan.Examples of many of these manipulations can be found for example in T.Greene, Protecting Groups in Organic Synthesis. Of course, amino acidsused as starting materials with reactive side chains are preferablyblocked to prevent undesired side reactions.

[0122] The compounds of the invention may have one or more chiralcenters. As a result, one may selectively prepare one optical isomer,including diastereomer and enantiomer, over another, for example bychiral starting materials, catalysts or solvents, or may prepare bothstereoisomers or both optical isomers, including diastereomers andenantiomers at once (a racemic mixture). Since the compounds of theinvention may exist as racemic mixtures, mixtures of optical isomers,including diastereomers and enantiomers, or stereoisomers may beseparated using known methods, such as chiral salts, chiralchromatography and the like.

[0123] In addition, it is recognized that one optical isomer, includingdiastereomer and enantiomer, or stereoisomer may have favorableproperties over the other. Thus when disclosing and claiming theinvention, when one racemic mixture is disclosed, it is clearlycontemplated that both optical isomers, including diastereomers andenantiomers, or stereoisomers substantially free of the other aredisclosed and claimed as well.

[0124] Methods of Use

[0125] Metalloproteases (MPs) found in the body operate, in part, bybreaking down the extracellular matrix, which comprises extracellularproteins and glycoproteins. These proteins and glycoproteins play animportant role in maintaining the size, shape, structure and stabilityof tissue in the body. Inhibitors of metalloproteases are useful intreating diseases caused, at least in part, by breakdown of suchproteins. It is known that MPs are intimately involved in tissueremodeling. As a result of this activity they have been said to beactive in many disorders involving either the:

[0126] breakdown of tissues; including degenerative diseases, such asarthritis, multiple sclerosis and the like; metastasis or mobility oftissues in the body:

[0127] the remodeling of tissues, including fibrotic disease, scarring,benign hyperplasia, and the like.

[0128] The compounds of the present invention treat disorders, diseasesand/or unwanted conditions which are characterized by unwanted orelevated activity by that class of proteases. For example the compoundscan be used to inhibit proteases which

[0129] destroy structural proteins (i.e. the proteins that maintaintissue stability and structure);

[0130] interfere in inter/intracellular signaling, including thoseimplicated in cytokine up-regulation, and/or cytokine processing and/orinflammation, tissue degradation and other maladies [Mohler K M, et al,Nature 370 (1994) 218-220, Gearing A J H, et al, Nature 370 (1994)555-557 McGeehan G M, et al, Nature 370 (1994) 558-561], and/or

[0131] facilitate processes which are undesired in the subject beingtreated, for example, the processes of sperm maturation, eggfertilization and the like.

[0132] As used herein, a “MP related disorder” or “a MP related disease”is one that involves unwanted or elevated MP activity in the biologicalmanifestation of the disease or disorder; in the biological cascadeleading to the disorder; or as a symptom of the disorder. This“involvement” of the MP includes;

[0133] The unwanted or elevated MP activity as a “cause” of the disorderor biological manifestation, whether the activity was elevatedgenetically, by infection, by autoimmunity, trauma, biomechanicalcauses, lifestyle [e.g. obesity] or by some other cause;

[0134] The MP as part of the observable manifestation of the disease ordisorder. That is, the disease or disorder is measurable in terms of theincreased MP activity, or from a clinical standpoint, unwanted orelevated MP levels indicate the disease. MPs need not be the “hallmark”of the disease or disorder;

[0135] The unwanted or elevated MP activity is part of the biochemicalor cellular cascade that results or relates to the disease or disorder.In this respect, inhibition of the MP activity interrupts the cascade,and thus controls the disease.

[0136] Advantageously, many MPs are not distributed evenly throughoutthe body. Thus the distribution of MPs expressed in various tissues areoften specific to those tissues. For example, the distribution ofmetalloproteases implicated in the breakdown of tissues in the joints,is not the same as the distribution of metalloproteases found in othertissues. Thus, though not essential for activity or efficacy, certaindisorders preferably are treated with compounds that act on specific MPsfound in the affected tissues or regions of the body. For example, acompound which displays a higher degree of affinity and inhibition for aMP found in the joints (e.g. chondrocytes) would be preferred fortreatment of disease found there than other compounds which are lessspecific.

[0137] In addition, certain inhibitors are more bioavailable to certaintissues than others, and this judicious choice of inhibitor, with theselectivity described above provides for specific treatment of thedisorder, disease or unwanted condition. For example, compounds of thisinvention vary in their ability to penetrate into the central nervoussystem. Thus compounds may be selected to produce effects mediatedthrough MPs found specifically outside the central nervous system.

[0138] Determination of the specificity of a MP inhibitor of a certainMP is within the skill of the artisan in that field. Appropriate assayconditions can be found in the literature. Specifically assays are knownfor stromelysin and collagenase. For example, U.S. Pat. No. 4,743,587references the procedure of Cawston, et al., Anal Biochem (1979)99:340-345. The use of a synthetic substrate in an assay is described byWeingarten, H., et al., Biochem Biophy Res Comm (1984) 139:1184-1187.Any standard method for analyzing the breakdown of structural proteinsby MPs can, of course, be used. The ability of compounds of theinvention to inhibit metalloprotease activity can, of course, be testedin the assays found in the literature, or variations thereof. Isolatedmetalloprotease enzymes can be used to confirm the inhibiting activityof the invention compounds, or crude extracts which contain the range ofenzymes capable of tissue breakdown can be used.

[0139] As a result of the MP inhibitory effect of the compounds of theinvention, the compounds of the invention are also useful in treatingthe following disorders by virtue of their metalloprotease activity.

[0140] The compounds of this invention are also useful for theprophylactic or acute treatment. They are administered in any way theskilled artisan in the fields of medicine or pharmacology would desire.It is immediately apparent to the skilled artisan that preferred routesof administration will depend upon the disease state being treated, andthe dosage form chosen. Preferred routes for systemic administrationinclude administration perorally or parenterally.

[0141] However, the skilled artisan will readily appreciate theadvantage of administering the MP inhibitor directly to the affectedarea for many disorders. For example, it may be advantageous toadminister MP inhibitors directly to the area of the disease orcondition as in area affected by surgical trauma (e. g., angioplasty),area affected by scarring or burn (e.g., topical to the skin),

[0142] Because the remodeling of bone involves MPs, the compounds of theinvention are useful in preventing prosthesis loosening. It is known inthe art that over time prostheses loosen, become painful, and may resultin further bone injury, thus demanding replacement. The need forreplacement of such prostheses includes those such as in, jointreplacements (for example hip, knee and shoulder replacements), dentalprosthesis, including dentures, bridges and prosthesis secured to themaxilla and/or mandible.

[0143] MPs are also active in remodeling of the cardiovascular system(for example, in congestive heart failure). It has been suggested thatone of the reasons angioplasty has a higher than expected long termfailure rate (reclosure over time) is that MP activity is not desired oris elevated in response to what may be recognized by the body as“injury” to the basement membrane of the vessel. Thus regulation of MPactivity in indications such as dilated cardiomyopathy, congestive heartfailure, atherosclerosis, plaque rupture, reperfusion injury, ischemia,chronic obstructive pulmonary disease, angioplasty restenosis and aorticaneurysm may increase long term success of any other treatment, or maybe a treatment in itself

[0144] In skin care, MPs are implicated in the remodeling or “turnover”of skin. As a result, the regulation of MPs improves treatment of skinconditions including but not limited to, wrinkle repair, regulation andprevention and repair of ultraviolet induced skin damage. Such atreatment includes prophylactic treatment or treatment before thephysiological manifestations are obvious. For example, the MP may beapplied as a pre-exposure treatment to prevent ultraviolet. damageand/or during or after exposure to prevent or minimize post-exposuredamage. In addition, MPs are implicated in skin disorders and diseasesrelated to abnormal tissues that result from abnormal turnover, whichincludes metalloprotease activity, such as epidermolysis bullosa,psoriasis, scleroderma and atopic dermatitis. The compounds of theinvention are also useful for treating the consequences of “normal”injury to the skin including scarring or “contraction” of tissue, forexample, following burns. MP inhibition is also useful in surgicalprocedures involving the skin for prevention of scarring, and promotionof normal tissue growth including in such applications as limbreattachment and refractory surgery (whether by laser or incision).

[0145] In addition, MPs are related to disorders involving irregularremodeling of other tissues, such as bone, for example, in otosclerosisand/or osteoporosis, or for specific organs, such as in liver cirrhosisand fibrotic lung disease. Similarly in diseases such as multiplesclerosis, MPs may be involved in the irregular modeling of blood brainbarrier and/or myelin sheaths of nervous tissue. Thus regulating MPactivity may be used as a strategy in treating, preventing andcontrolling such diseases.

[0146] MPs are also thought to be involved in many infections, includingcytomegalovirus; [CMV] retinitis; HIV, and the resulting syndrome, AIDS.

[0147] MPs may also be involved in extra vascularization wheresurrounding tissue needs to be broken down to allow new blood vesselssuch as in angiofibroma and hemangioma.

[0148] Since MPs break down the extracellular matrix, it is contemplatedthat inhibitors of these enzymes can be used as birth control agents,for example in preventing ovulation, in preventing penetration of thesperm into and through the extracellular milieu of the ovum,implantation of the fertilized ovum and in preventing sperm maturation.

[0149] In addition they are also contemplated to be useful in preventingor stopping premature labor and delivery.

[0150] Since MPs are implicated in the inflammatory response, and in theprocessing of cytokines the compounds are also useful asanti-inflammatories, for use in disease where inflammation is prevalentincluding, inflammatory bowel disease, Crohn's disease, ulcerativecolitis, pancreatitis, diverticulitis, asthma or related lung disease,rheumatoid arthritis, gout and Reiter's Syndrome.

[0151] Where autoimmunity is the cause of the disorder, the immuneresponse often triggers MP and cytokine activity. Regulation of MPs intreating such autoimmune disorders is a useful treatment strategy. ThusMP inhibitors can be used for treating disorders including, lupuserythmatosis, ankylosing spondylitis, and autoimmune keratitis.Sometimes the side effects of autoimmune therapy result in exacerbationof other conditions mediated by MPs, here MP inhibitor therapy iseffective as well, for example, in autoimmune-therapy-induced fibrosis.

[0152] In addition, other fibrotic diseases lend themselves to this typeof therapy, including pulmonary disease, bronchitis, emphysema, cysticfibrosis, acute respiratory distress syndrome (especially the acutephase response).

[0153] Where MPs are implicated in the undesired breakdown of tissue byexogenous agents, these can be treated with MP inhibitors. For example,they are effective as rattle snake bite antidote, as anti-vessicants, intreating allergic inflammation, septicemia and shock. In addition, theyare useful as antiparasitics (e.g., in malaria) and antiinfectives. Forexample, they are thought to be useful in treating or preventing viralinfection, including infection which would result in herpes, “cold”(e.g., rhinoviral infection), meningitis, hepatitis, HIV infection andAIDS.

[0154] MP inhibitors are also thought to be useful in treatingAlzheimer's disease, amyotrophic lateral sclerosis (ALS), musculardystrophy, complications resulting from or arising out of diabetes,especially those involving loss of tissue viability, coagulation, Graftvs. Host disease, leukemia, cachexia, anorexia, proteinuria, and perhapsregulation of hair growth.

[0155] For some diseases, conditions or disorders MP inhibition iscontemplated to be a preferred method of treatment. Such diseases,conditions or disorders include, arthritis (including osteoarthritis andrheumitoid arthritis), cancer (especially the prevention or arrest oftumor growth and metastasis), ocular disorders (especially cornealulceration, lack of corneal healing, macular degeneration, andpterygium), and gum disease (especially periodontal disease, andgingivitis)

[0156] Compounds preferred for, but not limited to, the treatment ofarthritis (including osteoarthritis and rheumatoid arthritis) are thosecompounds that are selective for the metalloproteases and thedisintegrin metalloproteases.

[0157] Compounds preferred for, but not limited to, the treatment ofcancer (especially the prevention or arrest of tumor growth andmetastasis) are those compounds that preferentially inhibit gelatinasesor type IV collagenases.

[0158] Compounds preferred for, but not limited to, the treatment ofocular disorders (especially corneal ulceration, lack of cornealhealing, macular degeneration, and pterygium) are those compounds thatbroadly inhibit metalloproteases. Preferably these compounds areadministered topically, more preferably as a drop or gel.

[0159] Compounds preferred for, but not limited to, the treatment of gumdisease (especially periodontal disease, and gingivitis) are thosecompounds that preferentially inhibit collagenases.

[0160] Compositions:

[0161] The compositions of the invention comprise:

[0162] (a) a safe and effective amount of a compound of Formula (I); and

[0163] (b) a pharmaceutically-acceptable carrier.

[0164] As discussed above, numerous diseases are known to be mediated byexcess or undesired metalloprotease activity. These include tumormetastasis, osteoarthritis, rheumatoid arthritis, skin inflammation,ulcerations, particularly of the cornea, reaction to infection,periodontitis and the like. Thus, the compounds of the invention areuseful in therapy with regard to conditions involving this unwantedactivity.

[0165] The invention compounds can therefore be formulated intopharmaceutical compositions for use in treatment or prophylaxis of theseconditions. Standard pharmaceutical formulation techniques are used,such as those disclosed in Remington's Pharmaceutical Sciences, MackPublishing Company, Easton, Pa., latest edition.

[0166] A “safe and effective amount” of a Formula (I) compound is anamount that is effective, to inhibit metalloproteases at the site(s) ofactivity, in a mammal subject, without undue adverse side effects (suchas toxicity, irritation, or allergic response), commensurate with areasonable benefit/risk ratio when used in the manner of this invention.The specific “safe and effective amount” will, obviously, vary with suchfactors as the particular condition being treated, the physicalcondition of the patient, the duration of treatment, the nature ofconcurrent therapy (if any), the specific dosage form to be used, thecarrier employed, the solubility of the Formula (I) compound therein,and the dosage regimen desired for the composition.

[0167] In addition to the subject compound, the compositions of thesubject invention contain a pharmaceutically-acceptable carrier. Theterm “pharmaceutically-acceptable carrier”, as used herein, means one ormore compatible solid or liquid filler diluents or encapsulatingsubstances which are suitable for administration to a mammal. The term“compatible”, as used herein, means that the components of thecomposition are capable of being commingled with the subject compound,and with each other, in a manner such that there is no interaction whichwould substantially reduce the pharmaceutical efficacy of thecomposition under ordinary use situations. Pharmaceutically-acceptablecarriers must, of course, be of sufficiently high purity andsufficiently low toxicity to render them suitable for administration tothe aminal, preferably mammal being treated.

[0168] Some examples of substances which can serve aspharmaceutically-acceptable carriers or components thereof are sugars,such as lactose, glucose and sucrose; starches, such as corn starch andpotato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; vegetable oils, such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil and oil oftheobroma; polyols such as propylene glycol, glycerine, sorbitol,mannitol, and polyethylene glycol; alginic acid; emulsifiers, such asthe TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents;flavoring agents; tableting agents, stabilizers; antioxidants;preservatives; pyrogen-free water; isotonic saline; and phosphate buffersolutions.

[0169] The choice of a pharmaceutically-acceptable carrier to be used inconjunction with the subject compound is basically determined by the waythe compound is to be administered.

[0170] If the subject compound is to be injected, the preferredpharmaceutically-acceptable carrier is sterile, physiological saline,with blood-compatible suspending agent, the pH of which has beenadjusted to about 7.4.

[0171] In particular, pharmaceutically-acceptable carriers for systemicadministration include sugars, starches, cellulose and its derivatives,malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils,polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonicsaline, and pyrogen-free water. Preferred carriers for parenteraladministration include propylene glycol, ethyl oleate, pyrrolidone,ethanol, and sesame oil. Preferably, the pharmaceutically-acceptablecarrier, in compositions for parenteral administration, comprises atleast about 90% by weight of the total composition.

[0172] The compositions of this invention are preferably provided inunit dosage form. As used herein, a “unit dosage form” is a compositionof this invention containing an amount of a Formula (I) compound that issuitable for administration to a aminal, preferably mammal subject, in asingle dose, according to good medical practice. These compositionspreferably contain from about 5 mg (milligrams) to about 1000 mg, morepreferably from about 10 mg to about 500 mg, more preferably from about10 mg to about 300 mg, of a Formula (I) compound.

[0173] The compositions of this invention may be in any of a variety offorms, suitable (for example) for oral, rectal, topical, nasal, ocularor parenteral administration. Depending upon the particular route ofadministration desired, a variety of pharmaceutically-acceptablecarriers well-known in the art may be used. These include solid orliquid fillers, diluents, hydrotropes, surface-active agents, andencapsulating substances. Optional pharmaceutically-active materials maybe included, which do not substantially interfere with the inhibitoryactivity of the Formula (I) compound. The amount of carrier employed inconjunction with the Formula (I) compound is sufficient to provide apractical quantity of material for administration per unit dose of theFormula (I) compound. Techniques and compositions for making dosageforms useful in the methods of this invention are described in thefollowing references, all incorporated by reference herein: ModernPharmaceutics, Chapters 9 and 10 (Banker & Rhodes, editors, 1979);Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); andAnsel, Introduction to Pharmaceutical Dosage Forms 2d Edition (1976).

[0174] In addition to the subject compound, the compositions of thesubject invention contain a pharmaceutically-acceptable carrier. Theterm “pharmaceutically-acceptable carrier”, as used herein, means one ormore compatible solid or liquid filler diluents or encapsulatingsubstances which are suitable for administration to a aminal, preferablymammal. The term “compatible”, as used herein, means that the componentsof the composition are capable of being commingled with the subjectcompound, and with each other, in a manner such that there is nointeraction which would substantially reduce the pharmaceutical efficacyof the composition under ordinary use situations.Pharmaceutically-acceptable carriers must, of course, be of sufficientlyhigh purity and sufficiently low toxicity to render them suitable foradministration to the aminal, preferably mammal being treated.

[0175] Some examples of substances which can serve aspharmaceutically-acceptable carriers or components thereof are sugars,such as lactose, glucose and sucrose; starches, such as corn starch andpotato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; vegetable oils, such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil and oil oftheobroma; polyols such as propylene glycol, glycerine, sorbitol,mannitol, and polyethylene glycol; alginic acid; emulsifiers, such asthe TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents;flavoring agents; tableting agents, stabilizers; antioxidants;preservatives; pyrogen-free water; isotonic saline; and phosphate buffersolutions.

[0176] The choice of a pharmaceutically-acceptable carrier to be used inconjunction with the subject compound is basically determined by the waythe compound is to be administered.

[0177] If the subject compound is to be injected, the preferredpharmaceutically-acceptable carrier is sterile, physiological saline,with blood-compatible suspending agent, the pH of which has beenadjusted to about 7.4.

[0178] Various oral dosage forms can be used, including such solid formsas tablets, capsules, granules and bulk powders. These oral formscomprise a safe and effective amount, usually at least about 5%, andpreferably from about 25% to about 50%, of the Formula (I) compound.Tablets can be compressed, tablet triturates, enteric-coated,sugar-coated, film-coated, or multiple-compressed, containing suitablebinders, lubricants, diluents, disintegrating agents, coloring agents,flavoring agents, flow-inducing agents, and melting agents. Liquid oraldosage forms include aqueous solutions, emulsions, suspensions,solutions and/or suspensions reconstituted from non-effervescentgranules, and effervescent preparations reconstituted from effervescentgranules, containing suitable solvents, preservatives, emulsifyingagents, suspending agents, diluents, sweeteners, melting agents,coloring agents and flavoring agents.

[0179] The pharmaceutically-acceptable carrier suitable for thepreparation of unit dosage forms for peroral administration arewell-known in the art. Tablets typically comprise conventionalpharmaceutically-compatible adjuvants as inert diluents, such as calciumcarbonate, sodium carbonate, mannitol, lactose and cellulose; binderssuch as starch, gelatin and sucrose; disintegrants such as starch,alginic acid and croscarmelose; lubricants such as magnesium stearate,stearic acid and talc. Glidants such as silicon dioxide can be used toimprove flow characteristics of the powder mixture. Coloring agents,such as the FD&C dyes, can be added for appearance. Sweeteners andflavoring agents, such as aspartame, saccharin, menthol, peppermint, andfruit flavors, are useful adjuvants for chewable tablets. Capsulestypically comprise one or more solid diluents disclosed above. Theselection of carrier components depends on secondary considerations liketaste, cost, and shelf stability, which are not critical for thepurposes of the subject invention, and can be readily made by a personskilled in the art.

[0180] Peroral compositions also include liquid solutions, emulsions,suspensions, and the like The pharmaceutically-acceptable carrierssuitable for preparation of such compositions are well known in the art.Typical components of carriers for syrups, elixirs, emulsions andsuspensions include ethanol, glycerol, propylene glycol, polyethyleneglycol, liquid sucrose, sorbitol and water. For a suspension, typicalsuspending agents include methyl cellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth and sodium alginate; typicalwetting agents include lecithin and polysorbate 80; and typicalpreservatives include methyl paraben and sodium benzoate. Peroral liquidcompositions may also contain one or more components such as sweeteners,flavoring agents and colorants disclosed above.

[0181] Such compositions may also be coated by conventional methods,typically with pH or time-dependent coatings, such that the subjectcompound is released in the gastrointestinal tract in the vicinity ofthe desired topical application, or at various times to extend thedesired action. Such dosage forms typically include, but are not limitedto, one or more of cellulose acetate phthalate, polyvinylacetatephthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose,Eudragit coatings, waxes and shellac.

[0182] Compositions of the subject invention may optionally includeother drug actives.

[0183] Other compositions useful for attaining systemic delivery of thesubject compounds include sublingual, buccal and nasal dosage forms.Such compositions typically comprise one or more of soluble fillersubstances such as sucrose, sorbitol and mannitol; and binders such asacacia, microcrystalline cellulose, carboxymethyl cellulose andhydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners,colorants, antioxidants and flavoring agents disclosed above may also beincluded.

[0184] The compositions of this invention can also be administeredtopically to a subject, e.g., by the direct laying on or spreading ofthe composition on the epidermal or epithelial tissue of the subject, ortransdermally via a “patch”. Such compositions include, for example,lotions, creams, solutions, gels and solids. These topical compositionspreferably comprise a safe and effective amount, usually at least about0.1%, and preferably from about 1% to about 5%, of the Formula (I)compound. Suitable carriers for topical administration preferably remainin place on the skin as a continuous film, and resist being removed byperspiration or immersion in water. Generally, the carrier is organic innature and capable of having dispersed or dissolved therein the Formula(I) compound. The carrier may include pharmaceutically-acceptableemolients, emulsifiers, thickening agents, solvents and the like.

[0185] Methods of Administration:

[0186] This invention also provides methods of treating or preventingdisorders associated with excess or undesired metalloprotease activityin an animal, preferably mammal subject, by administering a safe andeffective amount of a Formula (I) compound to said subject. As usedherein, a “disorder associated with excess or undesired metalloproteaseactivity” is any disorder characterized by degradation of proteins. Themethods of the invention are useful in treating disorders such as (forexample) osteoarthritis, periodontitis, corneal ulceration, tumorinvasion, and rheumatoid arthritis.

[0187] The Formula (I) compounds and compositions of this invention canbe administered topically or systemically. Systemic application includesany method of introducing Formula (I) compound into the tissues of thebody, e.g., intra-articular (especially in treatment of rheumatoidarthritis), intrathecal, epidural, intramuscular, transdermal,intravenous, intraperitoneal, subcutaneous, sublingual, rectal, and oraladministration. The Formula (1) compounds of the present invention arepreferably administered orally.

[0188] The specific dosage of inhibitor to be administered, as well asthe duration of treatment, and whether the treatment is topical orsystemic are interdependent. The dosage and treatment regimen will alsodepend upon such factors as the specific Formula (I) compound used, thetreatment indication, the ability of the Formula (I) compound to reachminimum inhibitory concentrations at the site of the metalloprotease tobe inhibited, the personal attributes of the subject (such as weight),compliance with the treatment regimen, and the presence and severity ofany side effects of the treatment.

[0189] Typically, for a human adult (weighing approximately 70kilograms), from about 5 mg to about 3000 mg, more preferably from about5 mg to about 1000 mg, more preferably from about 10 mg to about 100 mg,of Formula (I) compound are administered per day for systemicadministration. It is understood that these dosage ranges are by way ofexample only, and that daily administration can be adjusted depending onthe factors listed above.

[0190] A preferred method of administration for treatment of rheumatoidarthritis is oral or parenterally via intra-articular injection. As isknown and practiced in the art, all formulations for parenteraladministration must be sterile. For mammals, especially humans,(assuming an approximate body weight of 70 kilograms) individual dosesof from about 10 mg to about 1000 mg are preferred.

[0191] A preferred method of systemic administration is oral. Individualdoses of from about 10 mg to about 1000 mg, preferably from about 10 mgto about 300 mg are preferred.

[0192] Topical administration can be used to deliver the Formula (I)compound systemically, or to treat a subject locally. The amounts ofFormula (I) compound to be topically administered depends upon suchfactors as skin sensitivity, type and location of the tissue to betreated, the composition and carrier (if any) to be administered, theparticular Formula (I) compound to be administered, as well as theparticular disorder to be treated and the extent to which systemic (asdistinguished from local) effects are desired.

[0193] The inhibitors of the invention can be targeted to specificlocations where the metalloprotease is accumulated by using targetingligands. For example, to focus the inhibitors to metalloproteasecontained in a tumor, the inhibitor is conjugated to an antibody orfragment thereof which is immunoreactive with a tumor marker as isgenerally understood in the preparation of immunotoxins in general. Thetargeting ligand can also be a ligand suitable for a receptor which ispresent on the tumor. Any targeting ligand which specifically reactswith a marker for the intended target tissue can be used. Methods forcoupling the invention compound to the targeting ligand are well knownand are similar to those described below for coupling to carrier. Theconjugates are formulated and administered as described above.

[0194] For localized conditions, topical administration is preferred.For example, to treat ulcerated cornea, direct application to theaffected eye may employ a formulation as eyedrops or aerosol. Forcorneal treatment, the compounds of the invention can also be formulatedas gels, drops or ointments, or can be incorporated into collagen or ahydrophilic polymer shield. The materials can also be inserted as acontact lens or reservoir or as a subconjunctival formulation. Fortreatment of skin inflammation, the compound is applied locally andtopically, in a gel, paste, salve or ointment. The mode of treatmentthus reflects the nature of the condition and suitable formulations forany selected route are available in the art.

[0195] In all of the foregoing, of course, the compounds of theinvention can be administered alone or as mixtures, and the compositionsmay further include additional drugs or excipients as appropriate forthe indication.

[0196] Some of the compounds of the invention also inhibit bacterialmetalloproteases although generally at a lower level than that exhibitedwith respect to mammalian metalloproteases. Some bacterialmetalloproteases seem to be less dependent on the stereochemistry of theinhibitor, whereas substantial differences are found betweendiastereomers in their ability to inactivate the mammalian proteases.Thus, this pattern of activity can be used to distinguish between themammalian and bacterial enzymes.

[0197] Preparation and Use of Antibodies:

[0198] The invention compounds can also be utilized in immunizationprotocols to obtain antisera immunospecific for the invention compounds.As the invention compounds are relatively small, they are advantageouslycoupled to antigenically neutral carriers such as the conventionallyused keyhole limpet hemocyanin (KLH) or serum albumin carriers. Forthose invention compounds having a carboxyl functionality, coupling tocarrier can be done by methods generally known in the art. For example,the carboxyl residue can be reduced to an aldehyde and coupled tocarrier through reaction with sidechain amino groups in protein-basedcarriers, optionally followed by reduction of imino linkage formed. Thecarboxyl residue can also be reacted with sidechain amino groups usingcondensing agents such as dicyclohexyl carbodiimide or othercarbodiimide dehydrating agents.

[0199] Linker compounds can also be used to effect the coupling; bothhomobifunctional and heterobifunctional linkers are available fromPierce Chemical Company, Rockford, Ill. The resulting immunogeniccomplex can then be injected into suitable mammalian subjects such asmice, rabbits, and the like. Suitable protocols involve repeatedinjection of the immunogen in the presence of adjuvants according to aschedule which boosts production of antibodies in the serum. The titersof the immune serum can readily be measured using immunoassayprocedures, now standard in the art employing the invention compounds asantigens.

[0200] The antisera obtained can be used directly or monoclonalantibodies may be obtained by harvesting the peripheral bloodlymphocytes or the spleen of the immunized animal and immortalizing theantibody-producing cells, followed by identifying the suitable antibodyproducers using standard immunoassay techniques.

[0201] The polyclonal or monoclonal preparations are then useful inmonitoring therapy or prophylaxis regimens involving the compounds ofthe invention. Suitable samples such as those derived from blood, serum,urine, or saliva can be tested for the presence of the administeredinhibitor at various times during the treatment protocol using standardimmunoassay techniques which employ the antibody preparations of theinvention.

[0202] The invention compounds can also be coupled to labels such asscintigraphic labels, e.g., technetium 99 or I-131, using standardcoupling methods. The labeled compounds are administered to subjects todetermine the locations of excess amounts of one or moremetalloproteases in vivo. The ability of the inhibitors to selectivelybind metalloprotease is thus taken advantage of to map the distributionof these enzymes in situ. The techniques can also be employed inhistological procedures and the labeled invention compounds can be usedin competitive immunoassays.

[0203] The following non-limiting examples illustrate the compounds,compositions, and uses of the present invention.

EXAMPLES

[0204] Compounds are analyzed using ¹H and ¹³C NMR, Elemental analysis,mass spectra and/or IR spectra, as appropriate.

[0205] Typically inert solvents are used, preferably in dried form. Forexample, tetrahydrofuran (THF) is distilled from sodium andbenzophenone, diisopropylamine is distilled from calcium hydride and allother solvents are purchased as the appropriate grade. Chromatography isperformed on silica gel (70-230 mesh; Aldrich) or (230-400 mesh; Merck)as appropriate. Thin layer chromatography analysis (TLC) is performed onglass mounted silica gel plates (200-300 mesh; Baker) and visualizedwith UV or 5% phosphomolybdic acid in EtOH.

Example 1

[0206] Preparation ofN-Hydroxy-2,2-dimethyl-S,S-dioxo-4-[(4-methoxyphenyl)sulfonyl]thiazepine-3(S)-carboxamide

[0207] 1a. MethylN-[(4-methoxyphenyl)sulfonyl]-(2-hydroxypropyl)-D-penicillamine:D-Penicillamine (29.8 g, 0.2 mol) in 2N NaOH (135 mL, 0.27 mol, 1.35equiv) is stirred at 0° C. under an Argon atmosphere. A solution of2-bromopropanol (36.1 g, 0.26 mol, 1.3 equiv) in ethanol (200 mL) isslowly added dropwise at 0° C. The resulting solution is stirredovernight at room temperature and then the mixture is acidified to pH ˜6with 1 N HCl. The solvent is removed under reduced pressure to leave athick oil. The penicillamine adduct is then dissolved in dioxane (200mL) and water (200 mL) and stirred at room temperature. Triethylamine(58.6 g, 0.58 mol, 3 equiv) is then added to the reaction mixturefollowed by 4-methoxyphenylsulfonyl chloride (40.0 g, 0.193 mol). Theresulting homogeneous solution is stirred at room temperature for 18hours and then acidified to pH ˜2 with 1N HCl. The solution is pouredinto water and extracted with methylene chloride. The organic extractswere dried (MgSO₄) and concentrated to an oil under reduced pressure.The resulting oil is diluted in methanol (30 mL) and enough diazomethanein diethyl ether is added to form a yellow solution. The mixture isconcentrated under reduced pressure to leave a colorless oil.Purification of the resulting methyl ester is accomplished bychromatography on silica gel using 1/1 hexane/EtOAc as the eluent. Thedesired product is obtained as a clear, colorless oil.

[0208] 1b. Methyl4N-[(4-methoxyphenyl)sulfonyl]-2,2-dimethyl-thiazepine-3-carboxylate:The methyl ester 1a (30.0 g, 76.6 mmol) in THF (400 mL) is stirred atroom temperature and then triphenylphosphine (24.1 g, 91.9 mmol, 1.2equiv) followed by diethyl azodicarboxylate (14.7 g, 84.3 mmol, 1.1equiv) is added. The resulting solution is stirred at room temperaturefor 2 hours. The solvent is removed and then the thick yellow oil isdiluted with methylene chloride and silica gel (60 g) is added. Thesolvent is removed to leave a white powder. This powder is placed upon achromatography column and eluted with 8/2 hexane/EtOAc. The desiredproduct is obtained as a colorless oil. MS (ESI): 374 (M⁺+H), 391(M⁺+NH₄).

[0209] 1c.4-[(4-methoxyphenyl)sulfonyl]-2,2-dimethyl-thiazepine-3-carboxylic acid:The methyl ester 1b (26.7 g, 71.5 mmol) in pyridine (400 mL) is stirredat room temperature under an argon atmosphere. Lithium iodide (115 g,858 mmol, 12 equiv) is added and the resulting solution is heated toreflux for 3 h. The reaction mixture is cooled to room temperature andthen the solution is acidified with 1N HCl. The mixture is extractedwith methylene chloride and then the organic extracts were dried(Na₂SO₄) and concentrated to an oil under reduced pressure. The oil ispurified by column chromatography using 1/1 hexane/EtOAc as the eluentto provide the desired product as a light yellow oil. MS (ESI): 360(M⁺+H), 377 (M⁺+NH₄).

[0210] 1d.N-Hydroxy-4-[(4-methoxyphenyl)sulfonyl]-2,2-dimethyl-thiazepine-3-carboxamide:The carboxylic acid 1c (14.9 g, 41.6 mmol) in dichloromethane (200 mL)is stirred at room temperature and then oxalyl chloride (10.8 g, 85.2mmol, 2.05 equiv) and DMF (3.04 g, 41.6 mmol) are added. The resultingsolution is stirred at room temperature for 30 minutes. In a separateflask, hydroxylamine hydrochloride (11.6 g, 166 mmol, 4 equiv) in THF(50 mL) and water (10 mL) is stirred at 0° C. Triethylamine (25.3 g,249.6 mmol, 6 equiv) is added and the resulting solution is stirred at0° C. for 15 minutes. The acid chloride solution is next added to thehydroxylamine solution at 0° C. and the resulting mixture is allowed tostir overnight at room temperature. The reaction mixture is nextacidified with 1 N HCl and then extracted with dichloromethane. Theorganic extracts were dried (Na₂SO₄) and concentrated to a solid underreduced pressure. The solid is recrystallized from CH₃CN to provide awhite powder. MS (ESI): 392 (M⁺+NH₄), 375 (M⁺+H).

Example 2

[0211] Preparation ofN-Hydroxy-S,S-dioxo-4-[(4-methoxyphenyl)sulfonyl]-2,2-dimethyl-thiazepine-3-carboxamide

[0212] 2a.N-Hydroxy-S,S-dioxo-4-[(4-methoxyphenyl)sulfonyl]-2,2-dimethyl-thiazepine-3-carboxamide:The hydroxamic acid 1d (4.7 g, 12.55 mmol) is dissolved in chloroform(50 mL) at 0° C. in an ice bath. A solution of 32% peracetic acid (7.9mL, 37.65 mmol, 3.0 equiv in acetic acid) is added and the mixture isthen stirred at room temperature. An additional 3 equiv of 32% peraceticacid is added after 3 hours and the resulting mixture is stirredovernight. Once the reaction is complete, the peracetic acid is removedunder reduced pressure. The white solid is recrystallized withacetonitrile to provide a white powder. MS (ESI): 407 (M⁺+H).

Example 3

[0213] Preparation of3(S)-N-Hydroxy-N-methyl-2,2-dimethyl-4N-[(4-methoxyphenyl)sulfonyl]-thiazepine-3-carboxamide

[0214] 3a.3(S)-N-Hydroxy-N-methyl-2,2-dimethyl-4N-[(4-methoxyphenyl)sulfonyl]-thiazepine-3-carboxamide:The carboxylic acid 1c (1.10 g, 3.06 mmol) in dichloromethane (25 mL) isstirred at room temperature and then oxalyl chloride (0.80 g, 6.27 mmol,2.05 equiv) and DMF (0.22 g, 3.06 mmol) are added. The resultingsolution is stirred at room temperature for 30 minutes. In a separateflask, N-methylhydroxylamine hydrochloride (1.02 g, 12.24 mmol, 4 equiv)in THF (8 mL) and water (2 ML) are stirred at 0° C. Triethylamine (1.85g, 18.4 mmol, 6 equiv) is added and the resulting solution is stirred at0° C. for 15 minutes. The acid chloride solution is next added to thehydroxylamine solution at 0° C. and the resulting mixture is allowed tostir overnight at room temperature. The reaction mixture is acidifiedwith 1 N HCl and then extracted with dichloromethane. The organicextracts are dried (Na₂SO₄) and concentrated to a solid under reducedpressure. The solid is purified by reverse phase (C₁₈) HPLCchromatography to provide a white powder. MS (ESI): 389 (M⁺+H).

Example 4

[0215] Preparation ofN-Hydroxy-S,S-dioxo-2,2-dimethyl-4-[(4-bromophenyl)sulfonyl]thiazepine-3(S)-carboxamide

[0216] 4a. MethylN-[(4-bromophenyl)sulfonyl]-S-(2-hydroxypropyl)-D-penicillamine:D-Penicillamine (20.9 g, 134.0 mmol) in 2N NaOH (88 mL, 174.2 mmol, 1.35equiv) is stirred at 0° C. under an Argon atmosphere. A solution of2-bromopropanol (26.0 g, 187.7 mmol, 1.3 equiv) in ethanol (150 mL) isslowly added dropwise at 0° C. The resulting solution is stirredovernight at room temperature and then the mixture is acidified to pH ˜6with 1 N HCl. The solvent is removed under reduced pressure to leave athick oil. The penicillamine adduct is then dissolved in dioxane (150mL) and water (150 mL) and stirred at room temperature. Triethylamine(40.6 g, 402 mmol, 3 equiv) is then added to the reaction mixturefollowed by 4-bromophenylsulfonyl chloride (41.1 g, 160.8 mmol). Theresulting homogeneous solution is stirred at room temperature for 18hours and then acidified to pH ˜2 with 1N HCl. The solution is pouredinto water and extracted with methylene chloride. The organic extractswere dried (MgSO₄) and concentrated to an oil under reduced pressure.The resulting oil is diluted in methanol (30 mL) and enough diazomethanein diethyl ether is added to form a yellow solution. The mixture isconcentrated under reduced pressure to leave a colorless oil.Purification of the resulting methyl ester is accomplished bychromatography on silica gel using 40% ethyl acetate/60% hexane as theeluent. The desired product is obtained as a clear, colorless oil. MS(ESI): 440, 442 (M⁺+H), 457, 459 (M⁺+NH₄)

[0217] 4b. Methyl4N-[(4-bromophenyl)sulfonyl]-2,2-dimethyl-thiazepine-3-carboxylate: Themethyl ester 4a (31.0 g, 70.6 mmol) in THF (400 mL) is stirred at roomtemperature and then triphenylphosphine (22.2 g, 84.7 mmol, 1.2 equiv)followed by diethyl azodicarboxylate (13.5 g, 77.7 mmol, 1.1 equiv) isadded. The resulting solution is stirred at room temperature for 2hours. The solvent is removed and then the thick yellow oil is dilutedwith methylene chloride and silica gel (60 g) is added. The solvent isremoved to leave a white powder (absorb compound onto silica gel Thispowder is placed upon a chromatography column and eluted with 9/1hexane/EtOAc. The desired product is obtained as a colorless oil. MS(ESI): 422, 424 (M⁺+H), 439, 441 (M⁺+NH₄)

[0218] 4c.4-[(4-bromophenyl)sulfonyl]-2,2-dimethyl-thiazepine-3-carboxylic acid:The methyl ester 4b (24.8 g, 58.9 mmol) in pyridine (350 mL) is stirredat room temperature under an argon atmosphere. Lithium iodide (107 g,706 mmol, 12 equiv) is added and the resulting solution is heated toreflux for 3 h. The reaction mixture is cooled to room temperature andthen the solution is acidified with 1N HCl. The mixture is extractedwith methylene chloride and then the organic extracts were dried(Na₂SO₄) and concentrated to an oil under reduced pressure. The oil ispurified by column chromatography using 1/1 hexane/EtOAc as the eluentto provide the desired product as a light yellow oil. MS (ESI): 408, 410(M⁺+H), 425, 427 (M⁺+NH₄)

[0219] 4d.N-Hydroxy-4-[(4-bromophenyl)sulfonyl]-2,2-dimethyl-thiazepine-3-carboxamide:The carboxylic acid 4c (14.65 g, 36.0 mmol) in dichloromethane (200 mL)is stirred at room temperature and then oxalyl chloride (9.4 g, 73.8mmol, 2.05 equiv) and DMF (2.63 g, 36.0 mmol) were added. The resultingsolution is stirred at room temperature for 30 minutes. In a separateflask, hydroxylamine hydrochloride (10.0 g, 144.0 mmol, 4 equiv) in THF(50 mL) and water (10 mL) is stirred at 0° C. Triethylamine (21.8 g, 216mmol, 6 equiv) is added and the resulting solution is stirred at 0° C.for 15 minutes. The acid chloride solution is next added to thehydroxylamine solution at 0° C. and the resulting mixture is allowed tostir overnight at room temperature. The reaction mixture is nextacidified with 1 N HCl and then extracted with dichloromethane. Theorganic extracts were dried (Na₂SO₄) and concentrated to a solid underreduced pressure. The solid is recrystallized from acetonitrile toprovide a white powder. MS (ESI): 423, 425 (M⁺+H).

Example 5

[0220] Preparation ofN-Hydroxy-S,S-dioxo-4-[(4-bromophenyl)sulfonyl]-2,2-dimethyl-thiazepine-3-carboxamide

[0221] 5a.N-Hydroxy-S,S-dioxo-4-[(4-bromophenyl)sulfonyl]-2,2-dimethyl-thiazepine-3-carboxamide:The hydroxamic acid (4.2 g, 9.9 mmol) is added to chloroform (50 mL).The suspension was cooled to 0° C. followed by the addition of peraceticacid (32% Aldrich solution) (6.4 mL, 29.7 mmol, 3.0 equiv). The solutionbecomes clear upon the addition of peracetic acid. The resultingsolution is then warmed to room temperature. After stirring overnight,the peracetic acid is removed under reduced pressure and the remainingsolid is recrystalized from acetonitrile. MS (ESI): 455, 457 (M⁺+H).

Example 6

[0222] Preparation ofN-Hydroxy-4-[(4-butoxyphenyl)sulfonyl]-2,2-dimethyl-thiazepine-3-carboxamide

[0223] 6a. MethylN-[(4-butoxyphenyl)sulfonyl]-S-(2-hydroxypropyl)-D-penicillamine:D-Penicillamine (2.5 g, 16.7 mmol) in 2N NaOH (18 mL, 1.35 equiv) isstirred at 0° C. under an Argon atmosphere. A solution of2-bromopropanol (3.24 g, 23.4 mmol, 1.4 equiv) in ethanol (20 mL) isslowly added dropwise at 0° C. The resulting solution is stirredovernight at room temperature and then the mixture is acidified to pH ˜6with 1 N HCl. The solvent is removed under reduced pressure to leave athick oil. The penicillamine adduct is then dissolved in dioxane (30 mL)and water (30 mL) and stirred at room temperature. Triethylamine (7.0mL, 50.1 mmol, 3 equiv) is then added to the reaction mixture followedby 4-n-butoxyphenylsulfonyl chloride (5.0 g, 20.1 mmol). The resultinghomogeneous solution is stirred at room temperature for 18 hours andthen acidified to pH ˜2 with 1N HCl. The solution is poured into waterand extracted with methylene chloride. The organic extracts are dried(MgSO₄) and concentrated to an oil under reduced pressure. The resultingoil is diluted in methanol (30 mL) and enough diazomethane in diethylether is added to form a yellow solution. The mixture is concentratedunder reduced pressure to leave a colorless oil. Purification of theresulting methyl ester is accomplished by chromatography on silica gelusing 3/2 hexane/EtOAc as the eluent. The desired product is obtained asa clear, colorless oil. MS (ESI): 434 (M⁺+H), 451 (M⁺+NH₄)

[0224] 6b. Methyl4N-[(4-butoxyphenyl)sulfonyl]-2,2-dimethyl-thiazepine-3-carboxylate: Themethyl ester 6a (3.3 g, 7.6 mmol) in THF (30 mL) is stirred at roomtemperature and then triphenylphosphine (2.39 g, 9.12 mmol, 1.2 equiv)followed by diethyl azodicarboxylate (1.45 mL, 8.36 mmol, 1.1 equiv) isadded. The resulting solution is stirred at room temperature for 2hours. The solvent is removed and then the thick yellow oil is dilutedwith methylene chloride and silica gel (10 g) is added. The solvent isremoved to leave a white powder. This powder is placed upon achromatography column and eluted with 9/1 hexane/EtOAc. The desiredproduct is obtained as a colorless oil. MS (ESI): 416 (M⁺+H), 433(M⁺+NH₄)

[0225] 6c.4-[(4-Butoxyphenyl)sulfonyl]-2,2-dimethyl-thiazepine-3-carboxylic acid:The methyl ester 6b (2.1 g, 5.06 mmol) in pyridine (50 mL) is stirred atroom temperature under an argon atmosphere. Lithium iodide (8.13 g, 60.7mmol, 12 equiv) is added and the resulting solution is heated to refluxfor 3 h. The reaction mixture is cooled to room temperature and then thesolution is acidified with 1N HCl. The mixture is extracted withmethylene chloride and then the organic extracts are dried (Na₂SO₄) andconcentrated to an oil under reduced pressure. The oil showed 95.5%purity on HPLC analysis using a solvent system of 40% A (95% water, 5%acetonitrile. 0.1% formic acid) and 60% B (20% water, 80% acetonitrile).The product is a colorless oil, which required no further purification.MS (ESI): 4402 (M⁺+H), 419 (M⁺+NH₄)

[0226] 6d.N-Hydroxy-4-[(4-butoxyphenyl)sulfonyl]-2,2-dimethyl-thiazepine-3-carboxamide:The carboxylic acid 6c (1.65 g, 4.15 mmol) in dichloromethane (20 mL) isstirred at room temperature and then oxalyl chloride (1.08 g, 8.5 mmol,2.05 equiv) and DMF (0.3 g, 4.15 mmol) are added. The resulting solutionis stirred at room temperature for 30 minutes. In a separate flask,hydroxylamine hydrochloride (1.25 g, 18.0 mmol, 4 equiv) in THF (20 mL)and water (5mL) is stirred at 0° C. Triethylamine (2.5 g, 24.9 mmol, 6equiv) is added and the resulting solution is stirred at 0° C. for 15minutes. The acid chloride solution is next added to the hydroxylaminesolution at 0° C. and the resulting mixture is allowed to stir overnightat room temperature. The reaction mixture is next acidified with 1 N HCland then extracted with dichloromethane. The organic extracts are dried(Na₂SO₄) and concentrated to a solid under reduced pressure. The solidis recrystallized from CH₃CN/H₂O to provide a white powder. MS (ESI):417 (M⁺+H), 434 (M⁺+NH₄)

Example 7

[0227] Preparation ofN-hydroxy-S,S-dioxo-2,2-dimethyl-[4-(4-butoxyphenyl)sulfonyl]-thiazepin-3-carboxamide

[0228] 7a.N-hydroxy-S,S-dioxo-2,2-dimethyl-[4-(4-butoxyphenyl)sulfonyl]-thiazepine-3-carboxamide:The hydroxamic acid (0.50 g, 1.2 mmol) is dissolved in chloroform (10mL) to form a suspension. The peracetic acid (0.855 g, 3.6 mmol, 3.0equiv) is next added, and the resulting clear solution is stirredovernight. The solvents are removed under reduced pressure to leave awhite solid. Purification is achieved through recrystallization withacetonitrile to form a white powder. MS (ESI): 449 (M⁺+H), 466 (M⁺+NH₄)

Example 8

[0229] Preparation ofN-Hydroxy-4-[(2-methyl-4-bromophenyl)sulfonyl]-2,2-dimethyl-thiazepine-3-carboxamide

[0230] 8a. MethylN-[(2-methyl-4-bromophenyl)sulfonyl]-S-(2-hydroxypropyl)-D-penicillamine:D-Penicillamine (3.0 g, 20.1 mmol) in 2N NaOH (18 mL, 1.35 equiv) isstirred at 0° C. under an Argon atmosphere. A solution of2-bromopropanol (3.91 g, 28.1 mmol, 1.4 equiv) in ethanol (20 mL) isslowly added dropwise at 0° C. The resulting solution is stirredovernight at room temperature and then the mixture is acidified to pH ˜6with 1 N HCl. The solvent is removed under reduced pressure to leave athick oil. The penicillamine adduct is then dissolved in dioxane (30 mL)and water (30 mL) and stirred at room temperature. Triethylamine (8.3mL, 60.0 mmol, 3 equiv) is then added to the reaction mixture followedby 2-methyl-4-bromophenylsulfonyl chloride (6.5 g, 24.1 mmol). Theresulting homogeneous solution is stirred at room temperature for 18hours and then acidified to pH ˜2 with 1N HCl. The solution is pouredinto water and extracted with methylene chloride. The organic extractsare dried (MgSO₄) and concentrated to an oil under reduced pressure. Theresulting oil is diluted in methanol (30 mL) and enough diazomethane indiethyl ether is added to form a yellow solution. The mixture isconcentrated under reduced pressure to leave a colorless oil.Purification of the resulting methyl ester is accomplished bychromatography on silica gel using 1/1 hexane/EtOAc as the eluent. Thedesired product is obtained as a clear, colorless oil. MS (ESI): 456,458 (M⁺+H), 473, 475 (M⁺+NH₄)

[0231] 8b. Methyl4N-[(2-methyl-4-bromophenyl)sulfonyl]-2,2-dimethyl-thiazepine-3-carboxylate:The methyl ester 8a (4.2 g, 9.4 mmol) in THF (30 mL) is stirred at roomtemperature and then triphenylphosphine (2.95 g, 10.3 mmol, 1.2 equiv)followed by diethyl azodicarboxylate (1.63 mL, 11.3 mmol, 1.1 equiv) isadded. The resulting solution is stirred at room temperature for 2hours. The solvent is removed and then the thick yellow oil is dilutedwith methylene chloride and silica gel (10 g) is added. The solvent isremoved to leave a white powder. This powder is placed upon achromatography column and eluted with 9/1 hexane[EtOAc. The desiredproduct is obtained as a colorless oil. MS (ESI): 436, 438 (M⁺+H), 453,455 (M⁺+NH₄)

[0232] 8c.4-[(2-Methyl-4-bromophenyl)sulfonyl]-2,2-dimethyl-thiazepine-3-carboxylicacid: The methyl ester 1b (2.4 g, 5.45 mmol) in pyridine (75 mL) isstirred at room temperature under an argon atmosphere. Lithium iodide(8.69 g, 65.4 mmol, 12 equiv) is added and the resulting solution isheated to reflux for 3 h. The reaction mixture is cooled to roomtemperature and then the solution is acidified with 1N HCl. The mixtureis extracted with methylene chloride and then the organic extracts aredried (Na₂SO₄) and concentrated to an oil under reduced pressure. Theoil showed 97% purity on HPLC analysis using a solvent system of 40% A(95% water, 5% acetonitrile. 0.1% formic acid) and 60% B (20% water, 80%acetonitrile), the product had a retention time of 9.58. The product isa colorless oil, which required no further purification. MS (ESI): 422,424 (M⁺+H), 439, 441 (M⁺+NH₄)

[0233] 8d.N-Hydroxy-4-[(2-methyl-4-bromophenyl)sulfonyl]-2,2-dimethyl-thiazepine-3-carboxamide:The carboxylic acid 8c (1.65 g, 3.9 mmol) in dichloromethane (20 mL) isstirred at room temperature and then oxalyl chloride (1.01 g, 7.9 mmol,2.05 equiv) and DMF (0.28 g, 3.9 mmol) are added. The resulting solutionis stirred at room temperature for 30 minutes. In a separate flask,hydroxylamine hydrochloride (1.1 g, 15.6 mmol, 4 equiv) in THF (20 mL)and water (5 mL) is stirred at 0° C. Triethylamine (2.4 g, 23.4 mmol, 6equiv) is added and the resulting solution is stirred at 0° C. for 15minutes. The acid chloride solution is next added to the hydroxylaminesolution at 0° C. and the resulting mixture is allowed to stir overnightat room temperature. The reaction mixture is next acidified with 1 N HCland then extracted with dichloromethane. The organic extracts are dried(Na₂SO₄) and concentrated to a solid under reduced pressure. The solidis recrystallized from CH₃CN/H₂O to provide a white powder. MS (ESI):437, 439 (M⁺+H), 454, 456 (M⁺+NH₄)

Example 9

[0234] Preparation ofN-Hydroxy-6-hydroxy-2,2-dimethyl-S,S-dioxo-4-[(4-methoxyphenyl)sulfonyl]-thiazepine-3(S)-carboxamide

[0235] 9a. MethylN-[(4-methoxyphenyl)sulfonyl]-S-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-D-penicillamine:D-Penicillamine (9.56 g, 64.1 mmol) in 2N NaOH (41.7 mL, 83.3 mmol, 1.3equiv) is stirred at 0° C. under an Argon atmosphere. A solution of(S)-4-(bromomethyl)-2,2-dimethyl-1,3-dioxolane (15.0 g, 76.9 mol, 1.2equiv, Ref: Kawakami et al, J. Org. Chem. 1982, 47, 3581) in ethanol (30mL) is slowly added dropwise to the reaction mixture at 0° C. Theresulting solution is stirred overnight at room temperature and then themixture is acidified to pH ˜6 with 1 N HCl. The solvent is removed underreduced pressure to leave a thick oil. The penicillamine adduct is thendissolved in dioxane (75 mL) and water (75 mL) and stirred at roomtemperature. Triethylamine (19.5 g, 192.3 mmol, 3 equiv) is then addedto the reaction mixture followed by 4-methoxyphenylsulfonyl chloride(15.9 g, 76.9 mmol). The resulting homogeneous solution is stirred atroom temperature for 18 hours and then acidified to pH ˜2 with 1N HCl.The solution is poured into water and extracted with methylene chloride.The organic extracts are dried (MgSO₄) and concentrated to an oil underreduced pressure. The resulting oil is diluted in methanol (30 mL) andenough diazomethane in diethyl ether is added to form a yellow solution.The mixture is concentrated under reduced pressure to leave a colorlessoil. Purification of the resulting methyl ester is accomplished bychromatography on silica gel using 8/2 hexane/EtOAc as the eluent. Thedesired product is obtained as a clear, colorless oil. MS (ESI): 448(M⁺+H), 465 (M⁺+NH₄).

[0236] 9b. Methyl 2(S)-N-[(4-methoxyphenyl)sulfonyl]-S-(2,3-dihydroxypropyl)-D-penicillamineThe acetonide 9a (11.1 g, 24.8 mmol) in THF (50 mL) is stirred at roomtemperature and the 1N HCl is added The resulting mixture is stirredovernight at room temperature until all of the starting material isconsumed. The reaction mixture is concentrated to remove the THF andthen the aqueous layer is extracted with methylene chloride. The organicextracts are dried (Na₂SO₄) and concentrated to an oil under reducedpressure. No further purification is performed. The product (10.0 g,99%) is obtained as a colorless oil.

[0237] 9c. MethylN-[(4-methoxyphenyl)sulfonyl]-S-(2(S)-hydroxy-3-t-butyldimethylsiloxypropyl)-D-penicillamine:The diol 9b (10.0 g, 24.5 mmol) in methylene chloride (150 mL) isstirred at room temperature and then triethylamine (2.73 g, 27 mmol, 1.1equiv) and dimethylaminopyridine (100 mg, 0.04 equiv) is added. Thet-butyldimethylsilyl chloride (3.7 g, 24.5 mmol) is added and theresulting mixture is stirred at room temperature overnight. The reactionmixture is poured into dilute sodium bicarbonate solution and extractedwith methylene chloride. The organic extracts are dried (Na₂SO₄) andthen concentrated to an oil under reduced pressure. Purification of theoil is accomplished by chroatography on silica gel using 7/3 hexan/EtOAcas the eluent. The product is obtained as a clear, colorless oil.

[0238] 9d. MethylN-[(4-methoxyphenyl)sulfonyl]-S-(2(S)-methoxymethoxy-3-t-butyldimethylsiloxy-propyl)-D-penicillamine:Sodium iodide (12.0 g, 80 mmol, 4 equiv) is stirred in dimethoxyethane(120 mL) at room temperature and then chloromethyl methyl ether (8.2 g,102 mmol, 5.1 equiv) is added. A brown suspension formed which becamehot to touch. The resulting mixture is stirred for 10 minutes and thealcohol 9c (10.5 g, 20 mmol) and diisopropylethylamine (14.3 g, 110mmol, 5.5 equiv) in dimethoxyethane (30 mL) is added. The mixture isstirred at room temperature for 1 h. and then heated to reflux for 4 h.The reaction mixture is poured into saturated sodium bicarbonatesolution and then extracted with methylene chloride. The organicextracts re dried (Na₂SO₄) and then concentrated to an oil under reducedpressure. The oil is purified by chromatography on silica gel using 8/2hexne/EtOAc as the eluent. The product is obtained as a yellow oil.

[0239] 9e. MethylN-[(4-methoxyphenyl)sulfonyl]-S-(2(S)-methoxymethoxy-3-hydroxypropyl)-D-penicillamine:The silyl ether 9d (3.16 g, 5.58 mmol) in THF (25 mL) is cooled to 0° C.and then tetrabutylammonium fluoride (1.0 M in THF, 14 mL, 2.5 equiv) isadded. The resulting mixture is stirred at 0° C. for 30 minutes and thewarmed to room temperature. The reaction mixture is stirred for anadditional 3 h. The reaction mixture is poured into saturated sodiumbicarbonate solution and then extracted with methylene chloride. Theorganic extracts are dried (Na₂SO₄) and then concentrated to an oilunder reduced pressure. The oil is purified by chromatography on silicagel using 1/1 hexane/EtOAc as the eluent. The product is obtained as aclear, colorless oil.

[0240] 9f. Methyl6(S)-methoxymethyl-4N-[(4-methoxyphenyl)sulfonyl]-2,2-dimethyl-thiazepine-3(S)-carboxylate:The methyl ester 9e (1.9 g, 4.3 mmol) in THF (15 mL) is stirred at roomtemperature and then triphenylphosphine (1.35 g, 5.16 mmol, 1.2 equiv)followed by diethyl azodicarboxylate (0.82 g, 4.73 mmol, 1.1 equiv) isadded. The resulting solution is stirred at room temperature for 2hours. The solvent is removed and then the thick yellow oil is dilutedwith methylene chloride and silica gel (20 g) is added. The solvent isremoved to leave a white powder. This powder is placed upon achromatography column and eluted with 8/2 hexane/EtOAc. The desiredproduct is obtained as a colorless oil. MS (ESI): 434 (M⁺+H), 451(M⁺+NH₄).

[0241] 9g.6-Methoxymethyl-4-[(4-methoxyphenyl)sulfonyl]-2,2-dimethyl-thiazepine-3(S)-carboxylicacid: The methyl ester 9f (2.2 g, 5.07 mmol) in pyridine (40 mL) isstirred at room temperature under an argon atmosphere. Lithium iodide(8.15 g, 61.9 mmol, 12 equiv) is added and the resulting solution waheated to reflux for 3 h. The reaction mixture wa cooled to roomtemperature and then the solution wa acidified with 1N HCl. The mixturewa extracted with methylene chloride and then the organic extracts aredried (Na₂SO₄) and concentrated, to an oil under reduced pressure. Theoil wa purified by column chromatography using 1/1 hexane/EtOAc as theeluent to provide the desired product as a light yellow oil. MS (ESI):420 (M⁺+H), 437 (M⁺+NH₄), 442 (M⁺+Na).

[0242] 9h.N-Hydroxy-6-methoxymethyl-4-[(4-methoxyphenyl)sulfonyl]-2,2-dimethyl-thiazepine-3-carboxamide:The carboxylic acid 9g (2.35 g, 5.6 mmol) in acetonitrile (15 mL) isstirred at room temperature and then oxalyl chloride (1.46 g, 11.5 mmol,2.05 equiv) and DMF (0.41 g, 5.6 mmol) are added. The resulting solutionis stirred at room temperature for 30 minutes. In a separate flask,hydroxylamine hydrochloride (1.56 g, 22.4 mmol, 4 equiv) in THF (10 mL)and water (2 mL) is stirred at 0° C. Triethylamine (3.40 g, 33.6 mmol, 6equiv) is added and the resulting solution is stirred at 0° C. for 15minutes. The acid chloride solution is next added to the hydroxylaminesolution at 0° C. and the resulting mixture is allowed to stir overnightat room temperature. The reaction mixture is acidified with 1 N HCl andthen extracted with dichloromethane. The organic extracts are dried(Na₂SO₄) and concentrated to a solid under reduced pressure. The solidis purified by reverse phase HPLC using 60/40 water/acetonitrile as theeluent to provide a white powder. MS (ESI): 373 (M⁺+H).

Example 10

[0243] Preparation ofN-Hydroxy-S,S-dioxo-6-hydroxy-4-[(4-methoxyphenyl)sulfonyl]-2,2-dimethyl-thiazepine-3-carboxamide

[0244] 10a.N-Hydroxy-S,S-dioxo-6-hydroxy-4-[(4-methoxyphenyl)sulfonyl]-2,2-dimethyl-thiazepine-3-carboxamide:The hydroxamic acid 9h (1.30 g, 2.99 mmol) is dissolved in chloroform(50 mL) and the mixture is stirred at room temperature. A 32% solutionof peracetic acid (3.03 mL, 11.97 mmloes, 4.0 equiv) is added and theresulting mixture is stirred at room temperature. The solvent andremaining peracetic acid is removed under reduced pressure to leave thedesired product as a white solid. The solid is recrystallized fromacetonitrile to provide the product as a white crystalline solid. MS(ESI): 423 (M+H⁺).

Example 11

[0245] Preparation of3(S)—N-Hydroxy-2,2-dimethyl-4-[(4-methoxyphenyl)sulfonyl]octahydro-1,4-thiazonine-3-carboxamide

[0246] 11a. MethylN-[(4-methoxyphenyl)sulfonyl]-S-(2-hydroxypentyl)-D-penicillamine:D-Penicillamine (5.0 g, 33.5 mmol) in 2N NaOH (21.8 mL, 43.6 mmol, 1.3equiv) is stirred at 0° C. under an Argon atmosphere. A solution of1-chloropentanol (4.92 g, 40.2 mmol, 1.2 equiv) in ethanol (30 mL) isslowly added dropwise at 0° C. The resulting solution is stirredovernight at room temperature and then the mixture is acidified to pH ˜6with 1 N HCl. The solvent is removed under reduced pressure to leave athick oil. The penicillamine adduct is then dissolved in dioxane (100mL) and water (100 mL) and stirred at room temperature. Triethylamine(10.2 g, 100 mmol, 3 equiv) is then added to the reaction mixturefollowed by 4-methoxyphenylsulfonyl chloride (7.62 g, 36.9 mmol, 1.1equiv). The resulting homogeneous solution is stirred at roomtemperature for 18 hours and then acidified to pH ˜2 with 1N HCl. Thesolution is poured into water and extracted with methylene chloride. Theorganic extracts are dried (MgSO₄) and concentrated to an oil underreduced pressure. The resulting oil is diluted in methanol (20 mL) andenough diazomethane in diethyl ether is added to form a yellow solution.The mixture is concentrated under reduced pressure to leave a colorlessoil. Purification of the resulting methyl ester is accomplished bychromatography on silica gel using 6/4 hexane/EtOAc as the eluent. Thedesired product is obtained as a clear, colorless oil. MS (ESI): 420(M⁺+H), 437 (M⁺+NH₄).

[0247] 11b. Methyl3(S)—N-Hydroxy-2,2-dimethyl-4-[(4-methoxyphenyl)sulfonyl]octahydro-1,4-thiazonine-3-carboxylate:The methyl ester 11a (2.1 g, 5.0 mmol) in THF (50 mL) is stirred at roomtemperature and then triphenylphosphine (1.58 g, 6.0 mmol, 1.2 equiv)followed by diethyl azodicarboxylate (0.96 g, 5.50 mmol, 1.1 equiv) isadded. The resulting solution is stirred at room temperature for 18hours. The solvent is removed and then the thick yellow oil is dilutedwith methylene chloride and silica gel (15 g) is added. The solvent isremoved to leave a white powder. This powder is placed upon achromatography column and eluted with 8/2 hexane/EtOAc. The desiredproduct is obtained as a colorless oil. MS (ESI): 402 (M⁺+H), 419(M⁺+NH₄).

[0248] 11c.3(S)—N-Hydroxy-2,2-dimethyl-4-[(4-methoxyphenyl)sulfonyl]octahydro-1,4-thiazonine-3-carboxylicacid: The methyl ester 11b (0.44 g, 1.10 mmol) in pyridine (10 mL) isstirred at room temperature under an argon atmosphere. Lithium iodide(1.76 g, 13.1 mmol, 12 equiv) is added and the resulting solution isheated to reflux for 5 h. The reaction mixture is cooled to roomtemperature and then the solution is acidified with 1N HCl. The mixtureis extracted with methylene chloride and then the organic extracts aredried (Na₂SO₄) and concentrated to an oil under reduced pressure. Theoil is purified by column chromatography using 1/1 hexane/EtOAc as theeluent to provide the desired product as a light yellow oil. MS (ESI):388 (M⁺+H), 405 (M⁺+NH₄).

[0249] 11d.3(S)—N-Hydroxy-2,2-dimethyl-4-[(4-methoxyphenyl)sulfonyl]octahydro-1,4thiazonine-3-carboxamide:The carboxylic acid 11c (392 mg, 1.01 mmol) in dichloromethane (10 mL)is stirred at room temperature and then oxalyl chloride (0.263 g, 2.07mmol, 2.05 equiv) and DMF (73.9 mg, 1.01 mmol) are added. The resultingsolution is stirred at room temperature for 30 minutes. In a separateflask, hydroxylamine hydrochloride (3.3 g, 47.5 mmol, 4 equiv) in THF(50 mL) and water (10 mL) is stirred at 0° C. Triethylamine (615 mg,6.06 mmol, 6 equiv) is added and the resulting solution is stirred at 0°C. for 15 minutes. The acid chloride solution is next added to thehydroxylamine solution at 0° C. and the resulting mixture is allowed tostir overnight at room temperature. The reaction mixture is nextacidified with 1 N HCl and then extracted with dichloromethane. Theorganic extracts are dried (Na₂SO₄) and concentrated to a solid underreduced pressure. The solid is recrystallized from CH₃CN to provide awhite powder. MS (ESI): 378 (M⁺+NH₄), 361 (M⁺+H).

Example 12

[0250] Preparation ofN-Hydroxy-2-methyl-4N-[(4-methoxyphenyl)sulfonyl]-thiazepine-3-carboxamide

[0251] 12a. 4(S)-Methyl 2-tert-butyl-1,3-thiazolidine-4-carboxylate (1):D-Cysteine methyl ester hydrochloride (12.9 g, 75.2 mmol) andtrimethylacetaldehyde (7.12 g, 82.7 mmol) in petroleum ether (150 mL)was stirred at room temperature and then triethylamine (8.37 g, 82.7mmol) was added dropwise over a five minute period. The resultingheterogeneous mixture was stirred for 16 h. at reflux and water wasremoved with the aid of a Dean-Stark trap. The reaction mixture wascooled to room temperature and then filtered. The residue was washedwith diethyl ether. The resulting filtrate was concentrated to leave14.87 g (97%) of the desired product as a light yellow oil.

[0252] 12b. 2S, 4S-Methyl2-tert-butyl-1,3-thiazolidine-3-formyl-4-carboxylate (2): Thethiazolidine (14.8 g, 72.8 mmol) in formic acid (110 mL) and saodiumformate (5.45 g, 80 mmol, 1.1 equiv) was stirred at 0° C. and thenacetic anhydide (22.3 g, 218 mmol, 3 equiv) was added dropwise over a 45minute period. The resulting solution was then warmed to roomtemperature and stirred overnight. The mixture was concentrated underreduced pressure to leave a yellow oil. The oil was carefullyneutralized with saturated sodium bicarbonate solution and thenextracted with diethyl ether (3×200 mL). The combined ether extractswere dried (Na₂SO₄) and then concentrated to an oil under reducedpressure. The oil (13.2 g, 79%) crystallized upon standing.

[0253] 12c. 2S, 4S-Methyl2-tert-butyl-1,3-thiazolidine-3-formyl-4-methyl-4-carboxylate (3): Asolution of n-butyllithium (1.6 M, 25.8 mL, 41.2 mmol, 1.06 equiv) wasadded dropwise to a cold (−78° C.) solution of diisopropylamine (5.9 g,58.4 mmol, 1.5 equiv) in THF (180 mL). The resulting solution wasstirred at −78° C. for 10 minutes. The DMPU(1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone, 27 mL) was next addedand the now blue solution was stirred at −78° C. for 1 h. The reactionmixture was cooled to −90° C. and then the thiazolidine (9.0 g, 38.9mmol) in THF (10 mL) was slowly added. The mixture was stirred for anadditional 0.75 h at −90° C. and then methyl iodide (6.63 g, 46.7 mmol,1.2 equiv) was added over 5 minutes. The reaction mixture was stirred at−90° C. for 2 h. and then warmed to room temperature. The solvent wasremoved to leave an oil which was poured into brine (200 mL) andextracted with diethyl ether (3×200 mL). The combined organic extractswere dried (Na₂SO₄) and then concentrated to an oil under reducedpressure. Purification of the oil was accomplished by chromatography onsilica gel using 9/1 hexane/EtOAc as the eluent. The product (5.90 g,62%) was obtained as a clear, colorless oil.

[0254] 12d. (S)-2-Methylcysteine hydrochloride (4): The methyl ester(6.0 g, 24.6 mmol) was added to 5N HCl (110 mL) and the resultingmixture was heated to reflux for 3 days. The mixture was then cooled toroom temperature and the solvent was remved under reduced pressure toleave 3.62 g (87%) of a yellow solid.

[0255] 12e. MethylN-[(4-methoxyphenyl)sulfonyl]-S-(2-hydroxyethyl)2-methyl-D-cysteine (5)D-Penicillamine (14.9 g, 0.1 mol) in 2N NaOH (65 mL, 0.13 mol, 1.3equiv) was stirred at ° C. under an Argon atmosphere. A solution of2-bromopropanol (15 g, 0.12 mol, 1.2 equiv) in ethanol (100 mL) wasslowly added dropwise at 0° C. The resulting solution was stirredovernight at room temperature and then the mixture was acidified to pH˜6 with 1 N HCl. The solvent was removed under reduced pressure to leavea thick oil. The penicillamine adduct was then dissolved in dioxane (200mL) and water (200 mL) and stirred at room temperature. Triethylamine(29.8 g, 0.295 mol, 3 equiv) was then added to the reaction mixturefollowed by 4-methoxyphenylsulfonyl chloride (22.3 g, 0.108 mol, 1.1equiv). The resulting homogeneous solution was stirred at roomtemperature for 18 hours and then acidified to pH ˜2 with 1N HCl. Thesolution was poured into water and extracted with methylene chloride.The organic extracts were dried (MgSO₄) and concentrated to an oil underreduced pressure. The resulting oil was diluted in methanol (30 mL) andenough diazomethane in diethyl ether was added to form a yellowsolution. The mixture was concentrated under reduced pressure to leave acolorless oil. Purification of the resulting methyl ester wasaccomplished by chromatography on silica gel using 1/1 hexane/EtOAc asthe eluent. The desired product was obtained as a clear, colorless oil.

[0256] 12f. Methyl2-methyl-4N-[(4-methoxyphenyl)sulfonyl]-thiazepine-3-carboxylate (6) Themethyl ester (10.8 g, 28.6 mmol) in THF (200 mL) was stirred at roomtemperature and then triphenylphosphine (9.0 g, 34.3 mmol, 1.2 equiv)followed by diethyl azodicarboxylate (5.48 g, 31.5 mmol, 1.1 equiv) wasadded. The resulting solution was stirred at room temperature for 2hours. The solvent was removed and then the thick yellow oil was dilutedwith methylene chloride and silica gel (30 g) was added. The solvent wasremoved to leave a white powder. This powder was placed upon achromatography column and eluted with 8/2 hexane/EtOAc. The desiredproduct was obtained as a colorless oil. MS (ESI): 360 (M⁺+H), 377(M⁺+NH₄).

[0257] 12g.2-Methyl-4N-[(4-methoxyphenyl)sulfonyl]-thiazepine-3-carboxylic acid Themethyl ester (9.5 g, 26.4 mmol) in pyridine (150 mL) was stirred at roomtemperature under an argon atmosphere. Lithium iodide (42.4 g, 317 mmol,12 equiv) was added and the resulting solution was heated to reflux for3 h. The reaction mixture was cooled to room temperature and then thesolution was acidified with 1N HCl. The mixture was extracted withmethylene chloride and then the organic extracts were dried (Na₂SO₄) andconcentrated to an oil under reduced pressure. The oil was D purified bycolumn chromatography using 1/1 hexane/EtOAc as the eluent to providethe desired product as a light yellow oil.

[0258] 12h.N-Hydroxy-2-methyl-4N-[(4-methoxyphenyl)sulfonyl]-thiazepine-3-carboxamideThe carboxylic acid (4.1 g, 11.8 mmol) in dichloromethane (50 mL) wasstirred at room temperature and then oxalyl chloride (3.09 g, 24.3 mmol,2.05 equiv) and DMF (0.87 g, 11.8 mmol) were added. The resultingsolution was stirred at room temperature for 30 minutes. In a separateflask, hydroxylamine hydrochloride (3.3 g, 47.5 mmol, 4 equiv) in THF(50 mL) and water (10 mL) was stirred at 0° C. Triethylamine (7.16 g,70.8 mmol, 6 equiv) was added and the resulting solution was stirred at0° C. for 15 minutes. The acid chloride solution was next added to thehydroxylamine solution at 0° C. and the resulting mixture was allowed tostir overnight at room temperature. The reaction mixture was nextacidified with 1 N HCl and then extracted with dichloromethane. Theorganic extracts were dried (Na₂SO₄) and concentrated to a solid underreduced pressure. The solid was recrystallized from CH₃CN/H₂O to providea white powder. MS (ESI): 378 (M⁺+NH₄), 361 (M⁺+H).

Example 13

[0259] Preparation ofN-Hydroxy-1-(4-methoxyphenylsulfonyl)-3,3-dimethyl-hexahydro-1H-azepine-2-carboxamide

[0260] 13a. Methyl 7-methyl-3-oxo-6-octenoate: In a dry flask, sodiumhydride (17.44 g, 436 mmol) was added under argon and rinsed severaltimes with hexane to remove the mineral oil. A solution of ofdimethylcarbonate (35.66 g, 396 mmol) in ether (60 mL)was added. Thesuspension was stirred and heated to reflux. Next,6-methyl-5-hepten-2-one (25.2 g, 198 mmol) was added dropwise untilhydrogen began to evolve. The remaining ketone was added very slowlyover a period of several hours at reflux. Once the additon was complete,the solution was stirred for an additional 2 hours, and then allowed tostand at room temperature overnight. The mixture was cooled in an icebath and a solution of methanol (40 mL) in ether (200 mL) was addedcautiously. The reaction mixture remained in the ice bath for 1 houruntil all bubbling ceased. The reaction mixture was then stirred at roomtemperature for 2 hours. The resulting suspension was poured onto ice(320 g) and concentrated HCl (80 mL). The solution was extracted severaltimes with ether, the organic layers were washed with sodium bicarbonateand dried over magnesium sulfate and concetrated under reduced pressureto form an oil. Purification was achieved through distillation, theproduct distilled at 75° C. to 90° C. The product was obtained as aclear pale yellow oil. MS (ESI): 185 (M⁺+H), 202 (M⁺+NH₄).

[0261] 13b. Methyl 2,2-dimethyl-6-oxo-cyclohexanecarboxylate: The methylester 13a (16.3 g, 88.6 mmol) was dissolved in methylene chloride (600mL) and cooled to 0° C., followed by the addition of stannic chloride(34.5 g, 132.8 mmol). The reaction mixture stirred at room temperatureovernight. The reaction was diluted with ether (1000 mL) and washed with1N HCl several times and some water, the organic layer was dried overmagnesium sulfate and evaporated down under educed pressure. The residuewas purified on silica gel using eluents of hexane:ethyl acetate (95:5).MS (ESI): 185 (M⁺+H), 202 (M⁺+NH₄).

[0262] 13c. 6,6-Dimethyl-7-carbomethoxy-tetrahydro-2(3H)-azepinone: Theketo ester 13b (7.3 g, 39.7 mmol) is dissolved in chloroform (180 mL)and cooled to 0° C. Methanesulfonic acid (38.1 g, 397 mmol) was addedfollowed by the addition of sodium azide. The reaction mixture wasstirred at room temperature for 30 minutes and then heated to reflux for5 hours. Ice was added to the reaction mixture and stirred for severalminutes, this was followed by the addition of ammonium hydroxide untilthe reaction became basic. The mixture is then extracted with methylenechloride, and the organic layers are dried (MgSO₄) and concentratedunder reduced pressure to an oil. MS (ESI): 200 (M⁺+H).

[0263] 13d. 2-Hydroxymethyl-3,3-dimethyl-hexahydro-1H-azepine: Theketone 13c (3.75 g, 18.9 mmol) is dissolved in THF (100 mL) under anargon atmosphere at room temperature. Lithium aluminum hydride (1.5 g,37.7 mmol, 2 equiv) was next added slowly to the reaction mixture. Thereaction mixture was heated to reflux for 5 hours. The mixture wasquenched by the slow, dropwise addition of ethyl acetate until bubblingof the reaction mixture ceased. Then, water (1.5 mL) was added to thesolution. A 15% NaOH (1.5 mL) was next added followed by water (3.0 mL).The resulting heterogeneous mixture is then filtered, and the remainingorganic layer is diluted with water and extracted with ether. Theorganic layers are dried over sodium sulfate and concentrated underreduced pressure. MS (ESI): 158 (M⁺+H).

[0264] 13e.1-[(4-Methoxyphenyl)sulfonyl]-2-hydroxymethyl-3,3-dimethyl-hexahydro-1H-azepine:The alcohol 13d (2.9 g, 18.9 mmol) was dissolved in a 1:1 mixture ofwater and p-dioxane (100 mL), followed by the addition of4-methoxyphenylsulfonyl chloride (4.7 g, 22.6 mmol) and triethylamine(7.86 mL, 56.5 mmol). The reaction mixture was stirred overnight. Thereaction was quenched and acidified with 1N HCl to a pH ˜2. The mixturewas then diluted with water and extracted with methylene chloride. Theorganic layers were dried over magnesium sulfate, and concentrated underreduced pressure. The compound was purified by silica gel chromatographyusing hexane: ethyl acetate (3:2) as the eluent. MS (ESI): 328 (M⁺+H),345 (M⁺+NH₄).

[0265] 13f.1-[(4-Methoxyphenyl)sulfonyl]-3,3-dimethyl-hexahydro-1H-azepine-2-carboxylicacid: The alcohol 13e (0.40 g, 1.22 mmol) is dissolved in acetone (50mL) and freshly prepared 8N Jones reagent is added until the solutionsustains an orange/brown color as opposed to a green color. The reactionmixturE is then stirred overnight. Isopropanol is added to quench theexcess Jones reagent and a green solid precipitates out of solution. Thesolid is filtered through celite, and the liquid is concentrated underreduced pressure. The residue is then dissolved in chloroform and washedwith water several times. The orgnic layer is dried over magnesiumsulfate, and concentrated under reduced pressure. The product is carriedforward with no further purification. MS (ESI): 342 (M⁺+H), 359(M⁺+NH₄).

[0266] 13g.N-Hydroxy-1-[(4-methoxyphenyl)sulfonyl]-3,3-dimethyl-hexahydro-1H-azepine-2-carboxamide:The carboxylic acid 13f (0.37 g, 1.07 mmol) in dichloromethane (10 mL)was stirred at room temperature and then oxalyl chloride (0.28 g, 2.2mmol, 2.05 equiv) and DMF (0.08 g, 4.15 mmol) were added. The resultingsolution was stirred at room temperature for 30 minutes. In a separateflask, hydroxylamine hydrochloride (0.3 g, 4.28 mmol, 4 equiv) in THF(10 mL) and water (2 mL) was stirred at 0° C. Triethylamine (0.65 g,6.42 mmol, 6 equiv) was added and the resulting solution was stirred at0° C. for 15 minutes. The acid chloride solution was next added to thehydroxylamine solution at 0° C. and the resulting mixture was allowed tostir overnight at room temperature. The reaction mixture was nextacidified with 1 N HCl and then extracted with dichloromethane. Theorganic extracts were dried (Na₂SO₄) and concentrated to a solid underreduced pressure. The solid was recrystallized from CH₃CN/H₂O to providethe desired product as a white powder. MS (ESI): 357 (M⁺+H).

Example 14

[0267] Preparation ofN-Hydroxy-1-[(4methoxyphenyl)sulfonyl]-hexahydro-1H-azepine-2-carboxamide

[0268] 14a. 7-Carboxmethoxy-tetrahydro-2(3H)-azepinone: The ethyl2-cyclohexanone carboxylate (15.0 g, 88.12 mmol) is dissolved inchloroform (200 mL) and cooled to 0° C. Methanesulfonic acid (84.7 g,881.2 mmol) was added followed by the addition of sodium azide. Thereaction mixture was stirred at room temperature for 30 minutes and thenheated to reflux for 5 hours. Ice was added to the reaction mixture andthe resulting solution was stirred for several minutes. Ammoniumhydroxide was added until the reaction is made basic. The mixture isextracted with methylene chloride, and the organic layers are dried(MgSO₄) and concentrated under reduced pressure to an oil. MS (ESI): 186(M⁺+H).

[0269] 14b. 2-Hydroxymethyl-hexahydro-1H-azepine: The amide 14a (5.0 g,27.0 mmol) is dissolved in THF (100 mL) under an argon atmosphere atroom temperature. Lithium aluminum hydride (2.0 g, 54.0 mmol, 2 equiv)was then cautiously added. The reaction mixture was heated to reflux for5 hours. The mixture was quenched by the slow, dropwise addition ofethyl acetate until bubbling of the reaction mixture ceased. Then, water(2.0 mL) was added to the solution. A 15% NaOH (2.0 mL) was next addedfollowed by water (5.0 mL). The resulting homogeneous solution isfiltered, and the remaining organic layer is diluted with water andextracted with ether. The organic layers are dried over sodium sulfateand concentrated under reduced pressure.

[0270] 14c.1-[(4-Methoxyphenyl)sulfonyl]-2-hydroxymethyl-hexahydro-1H-azepine: Thealcohol 14b (3.0 g, 23.5 mmol) was dissolved in a 1:1 mixture of waterand p-dioxane (100 mL) followed by the addition of4-methoxyphenylsulfonyl chloride (5.8 g, 28.2 mmol) and triethylamine(9.8 mL, 70.5 mmol). The reaction mixture was left to stir overnight.The reaction was quenched and acidified with 1N HCl to a pH ˜2. Thereaction mixture was then diluted with water and extracted withmethylene chloride. The organic layers were dried over magnesiumsulfate, and concentrated under reduced pressure. The compound waspurified by silica gel chromatography using hexane:ethyl acetate (2:1)as the eluent. MS (ESI): 300 (M⁺+H), 317 (M⁺+NH₄).

[0271] 14d.1-[(4-Methoxyphenyl)sulfonyl]-hexahydro-1H-azepine-2-carboxylic acid:The alcohol 14c (1.3 g, 4.35 mmol) is dissolved in acetone (100 mL) at0° C. and freshly prepared 8N Jones reagent is added until the solutionsustains an orange/brown color as opposed to a green color. Theresulting mixture is then stirred overnight. Isopropanol is added toquench the excess Jones reagent and a green solid precipitates out. Thesolid is filtered through celite, and the liquid is concentrated underreduced pressure. The residue is then dissolved in chloroform and washedwith water several times. The organic layer is dried over magnesiumsulfate, and concetrated under reduced pressure. The product is carriedforward with no further purification. MS (ESI): 314 (M⁺+H), 331(M⁺+NH₄).

[0272] 14e.N-Hydroxy-1-[(4methoxyphenyl)sulfonyl]-hexahydro-1H-azepine-2-carboxamide:

[0273] The carboxylic acid 14d (1.11 g, 3.56 mmol) in dichloromethane(25 mL) was stirred at room temperature and then oxalyl chloride (0.93g, 7.2 mmol, 2.05 equiv) and DMF (0.260 g, 3.56 mmol) were added. Theresulting solution was stirred at room temperature for 30 minutes. In aseparate flask, hydroxylamine hydrochloride (0.99 g, 14.24 mmol, 4equiv) in THF (15 mL) and water (8 mL) was stirred at 0° C.Triethylamine (2.15 g, 21.4 mmol, 6 equiv) was added and the resultingsolution was stirred at 0° C. for 15 minutes. The acid chloride solutionwas next added to the hydroxylamine solution at 0° C. and the resultingmixture was allowed to stir overnight at room temperature. The reactionmixture was next acidified with 1 N HCl and then extracted withdichloromethane. The organic extracts were dried (Na₂SO₄) andconcentrated to a solid under reduced pressure. The solid wasrecrystallized from CH₃CN/H₂O to provide a white powder. MS (ESI): 429(M⁺+H).

Examples 15-101

[0274] The following (where W is nil) compounds are made using themethods described and exemplified above.

Y X W Ar n Example 15 3,3-(CH₃—)₂ S H 4-NO₂—C₆H₄— 1 Example 163,3-(CH₃—)₂ S H 4-i-BuO—C₆H₄— 1 Example 17 3,3-(CH₃—)₂ S H4-(C₆H₅)O—C₆H₄— 1 Example 18 3,3-(CH₃—)₂ S H 4-(4-F.C₆H₄)O—C₆H₄— 1Example 19 3,3-(CH₃—)₂ S H 4-(4-Cl-C₆H₄)O—C₆H₄— 1 Example 20 3,3-(CH₃—)₂S H 4-(4-Br-C₆H₄)O—C₆H₄— 1 Example 21 3,3-(CH₃—)₂ S H4-(4-Me-C₆H₄)O—C₆H₄— 1 Example 22 3,3-(CH₃—)₂ S H 4-(4-MeO—C₆H₄)O—C₆H₄—1 Example 23 3,3-(CH₃—)₂ S H 4-(4-CN-C₆H₄)O—C₆H₄— 1 Example 243,3-(CH₃—)₂ S H 4-(4-Me₂N—C₆H₄O)O—C₆H₄— 1 Example 25 3,3-(CH₃—)₂ S H4-EtO—C₆H₄— 1 Example 26 3,3-(CH₃—)₂ S H 4-i-PrO—C₆H₄— 1 Example 273,3-(CH₃—)₂ S H 4-n-PrO—C₆H₄— 1 Example 28 3,3-(CH₃—)₂ S H2-CH₃-4-Br-C₆H₃— 1 Example 29 3,3-(CH₃—)₂ S H 4-C₆H₅—C₆H₄— 1 Example 303,3-(CH₃—)₂ S H 4-(4-F—C₆H₅)—C₆H₄— 1 Example 31 3,3-(CH₃—)₂ S H4-(4-Cl-C₆H₅)—C₆H₄— 1 Example 32 3,3-(CH₃—)₂ S H 4-(4-Br-C₆H₅)—C₆H₄— 1Example 33 3,3-(CH₃—)₂ S H 4-(4-Me₂N—C₆H₄)—C₆H₄— 1 Example 343,3-(CH₃—)₂ S H 4-(4-CN—C₆H₄)—C₆H₄— 1 Example 35 3,3-(CH₃—)₂ S H4-(4-MeO—C₆H₄)—C₆H₄— 1 Example 36 3,3-(CH₃—)₂ S H 4-(4-C₅H₄N)O—C₆H₄— 1Example 37 3,3-(CH₃—)₂ S H 4-(3-C₅H₄N)O—C₆H₄— 1 Example 38 3,3-(CH₃—)₂ SH 4-(2-C₅H₄N)O—C₆H₄— 1 Example 39 3,3-(CH₃—)₂ S H C₆H₅CH₂CH₂— 1 Example40 3,3-(CH₃—)₂ S H C₆H₅CH₂— 1 Example 41 3,3-(CH₃—)₂ S H(4-C₅H₄N)CH₂CH₂— 1 Example 42 3,3-(CH₃—)₂ S H (2-C₅H₄N)CH₂CH₂— 1 Example43 3,3-(CH₃—)₂ S H 4-(C₆H₁₁)O—C₆H₄— 1 Example 44 3,3-(CH₃—)₂ S H4-(C₅H₁₁)O—C₆H₄— 1 Example 45 3,3-(CH₃—)₂ S H 4-(C₆H₁₁)O—C₆H₄— 1 Example46 3,3-(CH₃—)₂ S H 4-(CH₃OCH₂CH₂)O—C₆H₄— 1 Example 47 3,3-(CH₃—)₂ S H5-(2-pyridinyl)-2-thienyl- 1 Example 48 3,3-(CH₃—)₂ S H5-(3-isoxazolyl)-2-thienyl- 1 Example 49 3,3-(CH₃—)₂ S H5-(2-(methylthio)pyrimidin-4-yl)-2-thienyl- 1 Example 50 3,3-(CH₃—)₂ S H5-(3-(1-methyl-5-(trifluoromethyl)pyrazolyl)-2-thienyl- 1 Example 513,3-(CH₃—)₂ SO₂ H 4-NO₂—C₆H₄— 1 Example 52 3,3-(CH₃—)₂ SO₂ H4-i-BuO—C₆H₄— 1 Example 53 3,3-(CH₃—)₂ SO₂ H 4-(C₆H₅)O—C₆H₄— 1 Example54 3,3-(CH₃—)₂ SO₂ H 4-(4-F—C₆H₄)O—C₆H₄— 1 Example 55 3,3-(CH₃—)₂ SO₂ H4-(4-Cl-C₆H₄)O—C₆H₄— 1 Example 56 3,3-(CH₃—)₂ SO₂ H 4-(4-Br-C₆H₄)O—C₆H₄—1 Example 57 3,3-(CH₃—)₂ SO₂ H 4-(4-Me-C₆H₄)O—C₆H₄— 1 Example 583,3-(CH₃—)₂ SO₂ H 4-(4-MeO—C₆H₄)O—C₆H₄— 1 Example 59 3,3-(CH₃—)₂ SO₂ H4-(4-CN—C₆H₄)O—C₆H₄— 1 Example 60 3,3-(CH₃—)₂ SO₂ H4-(4-Me₂N—C₆H₄)O—C₆H₄— 1 Example 61 3,3-(CH₃—)₂ SO₂ H 4-EtO—C₆H₄— 1Example 62 3,3-(CH₃—)₂ SO₂ H 4-i-PrO—C₆H₄— 1 Example 63 3,3-(CH₃—)₂ SO₂H 4-n-PrO—C₆H₄— 1 Example 64 3,3-(CH₃—)₂ SO₂ H 2-CH₃-4-Br-C₆H₃— 1Example 65 3,3-(CH₃—)₂ SO₂ H 4-C₆H₅—C₆H₄— 1 Example 66 3,3-(CH₃—)₂ SO₂ H4-(4-F—C₆H₅)—C₆H₄— 1 Example 67 3,3-(CH₃—)₂ SO₂ H 4~(4-Cl-C₆H₅)—C₆H₄— 1Example 68 3,3-(CH₃—)₂ SO₂ H 4-(4-Br-C₆H₅)—C₆H₄— 1 Example 693,3-(CH₃—)₂ SO₂ H 4-(4-Me₂N—C₆H₄)—C₆H₄— 1 Example 70 3,3-(CH₃—)₂ SO₂ H4-(4-CN—C₆H₄)—C₆H₄— 1 Example 71 3,3-(CH₃—)₂ SO₂ H 4-(4-MeO—C₆H₄)—C₆H₄—1 Example 72 3,3-(CH₃—)₂ SO₂ H 4-(4-C₅H₄N)O—C₆H₄— 1 Example 733,3-(CH₃—)₂ SO₂ H 4-(3-C₅H₄N)O—C₆H₄— 1 Example 74 3,3-(CH₃—)₂ SO₂ H4-(2-C₅H₄N)O—C₆H₄— 1 Example 75 3,3-(CH₃—)₂ SO₂ H C₆H₅CH₂CH₂— 1 Example76 3,3-(CH₃—)₂ SO₂ H C₆H₅CH₂— 1 Example 77 3,3-(CH₃—)₂ SO₂ H(4-C₅H₄N)CH₂CH₂— 1 Example 78 3,3-(CH₃—)₂ SO₂ H (2-C₅H₄N)CH₂CH₂— 1Example 79 3,3-(CH₃—)₂ SO₂ H C₆H₅CH₂CH₂— 1 Example 80 3,3-(CH₃—)₂ SO₂ HC₆H₅CH₂— 1 Example 81 3,3-(CH₃—)₂ SO₂ H (4-C₅H₄N)CH₂CH₂— 1 Example 823,3-(CH₃—)₂ SO₂ H (2-C₅H₄N)CH₂CH₂— 1 Example 83 3,3-(CH₃—)₂ SO₂ H4-(C₆H₁₁)O—C₆H₄— 1 Example 84 3,3-(CH₃—)₂ SO₂ H 4-(C₅H₁₁)O—C₆H₄— 1Example 85 3,3-(CH₃—)₂ SO₂ H 4-(C₆H₁₁)O—C₆H₄— 1 Example 86 3,3-(CH₃—)₂SO₂ H 4-(CH₃OCH₂CH₂)O—C₆H₄— 1 Example 87 3,3-(CH₃—)₂ SO₂ H5-(2-pyridinyl)-2-thienyl- 1 Example 88 3,3-(CH₃—)₂ SO₂ H5-(3-isoxazolyl)-2-thienyl- 1 Example 89 3,3-(CH₃—)₂ SO₂ H5-(2-(methylthio)pyrimidin-4-yl)-2-thienyl- 1 Example 90 3,3-(CH₃—)₂ SO₂H 5-(3-(1-methyl-5-(trifluoromethyl)pyrazolyl)-2-thienyl- 1 Example 913,3-(CH₃—)₂ CH₂ H 4-(C₆H₅)O—C₆H₄— 1 Example 92 3,3-(CH₃—)₂ CH₂ H4-(4-F—C₆H₄)O—C₆H₄— 1 Example 93 3,3-(CH₃—)₂ CH₂ H 4-(4-Cl-C₆H₄)O—C₆H₄—1 Example 94 3,3-(CH₃—)₂ CH₂ H 4-(4-Br-C₆H₄)O—C₆H₄— 1 Example 953,3-(CH₃—)₂ CH₂ H 4-(4-Me-C₆H₄)O—C₆H₄— 1 Example 96 3,3-(CH₃—)₂ CH₂ H4-(4-MeO—C₆H₄)O—C₆H₄— 1 Example 97 3,3-(CH₃—)₂ CH₂ H4-(4-CN—C₆H₄)O—C₆H₄— 1 Example 98 3,3-(CH₃—)₂ CH₂ H4-(4-Me₂N—C₆H₄)O—C₆H₄— 1 Example 99 3,3-(CH₃—)₂ CH₂ H 4-(4-C₅H₄N)O—C₆H₄—1 Example 100 3,3-(CH₃—)₂ CH₂ H 4-(3-C₅H₄N)O—C₆H₄— 1 Example 1013,3-(CH₃—)₂ CH₂ H 4-(2-C₅H₄N)O—C₆H₄— 1

[0275] Methods:

[0276] Examples 15-50 are prepared analogously to Example 1 using theappropriately functionalized sulfonyl chloride. The sulfonyl chlorideswhich are used to prepare the above examples are either purchased fromcommercial sources or prepared via known methods. For example, the4-phenoxyphenylsulfonyl chloride used for the preparation of Example 17,was prepared as described by R. J. Cremlyn et al in Aust. J. Chem.,1979, 32, 445.52.

[0277] Examples 51-90 are prepared by oxidation of the correspondingsulfide (found in Examples 15-50). The oxidation proceeds in a manneranalogous to Example 2.

[0278] Examples 91-101 are prepared analogously to Example 13 using theappropriately functionalized sulfonyl chloride.

[0279] These examples provide the skilled artisan with sufficientguidance as to making the present invention and do not limit it in anyway.

[0280] Composition and Method of Use Examples

[0281] The compounds of the invention are useful to prepare compositionsfor the treatment of ailments and the like. The following compositionand method examples do not limit the invention, but provide guidance tothe skilled artisan to prepare and use the compounds, compositions andmethods of the invention. In each case the compounds formula I may besubstituted for the example compound shown below with similar results.

[0282] The methods of use exemplified do not limit the invention, butprovide guidance to the skilled artisan to use the compounds,compositions and methods of the invention. The skilled practitioner willappreciate that the examples provide guidance and may be varied based oncondition and the patient.

Example A

[0283] A tablet composition for oral administration, according to thepresent invention, is made comprising: Component Amount Example 2a 15.mg Lactose 120. mg  Maize Starch 70. mg Talc  4. mg Magnesium Stearate 1. mg

[0284] Other compounds having a structure according to Formula (I) areused with substantially similar results.

[0285] A human female subject weighing 60 kg (132 lbs), suffering fromrheumatoid arthritis, is treated by a method of this invention.Specifically, for 2 years, a regimen of three tablets per day isadministered orally to said subject.

[0286] At the end of the treatment period, the patient is examined andis found to have reduced inflammation, and improved mobility withoutconcomitant pain.

Example B

[0287] A capsule for oral administration, according to the presentinvention, is made comprising: Component Amount (% w/w) Example 1 15%Polyethylene glycol 85%

[0288] Other compounds having a structure according to Formula (I) areused with substantially similar results.

[0289] A human male subject weighing 90 kg (198 lbs), suffering fromosteoarthritis, is treated by a method of this invention. Specifically,for 5 years, a capsule containing 70 mg of Example 3 is administereddaily to said subject.

[0290] At the end of the treatment period, the patient is examined viaorthoscopy, and found to have no further advancement oferosion/fibrillation of the articular cartilage.

Example C

[0291] A saline-based composition for local administration, according tothe present invention, is made comprising: Component Amount (% w/w)Example 1  5% Polyvinyl alcohol 15% Saline 80%

[0292] Other compounds having a structure according to Formula (I) areused with substantially similar results.

[0293] A patient having deep corneal abrasion applies the drop to eacheye twice a day. Healing is speeded, with no visual sequelae.

Example D

[0294] An topical composition for local administration, according to thepresent invention, is made comprising: Component Composition (% w/v)Compound of Example 2b. 0.20 Benzalkonium chloride 0.02 Thimerosal 0.002d-Sorbitol 5.00 Glycine 0.35 Aromatics 0.075 Purified water q.s. Total =100.00 Total = 100.00

[0295] Any of the other compounds having a structure according toFormula (I) are used with substantially similar results.

[0296] A patient suffering from chemical burns applies the compositionat each dressing change (b.i.d.). Scarring is substantially diminished.

Example E

[0297] A inhalation aerosol composition, according to the presentinvention, is made comprising: Component Composition (% w/v) Compound ofExample 2c. 5.0 Alcohol 33.0 Ascorbic acid 0.1 Menthol 0.1 SodiumSaccharin 0.2 Propellant (F12, F114) q.s. Total 100.0

[0298] Any of the other compounds having a structure according toFormula (I) are used with substantially similar results.

[0299] An asthma sufferer sprays 0.01 mL via a pump actuator into themouth while inhaling. Asthma symptoms are diminished.

Example F

[0300] A topical opthalmic composition, according to the presentinvention, is made comprising: Component Composition (% w/v) Compound ofExample 1 0.10 Benzalkonium chloride 0.01 EDTA 0.05Hydroxyethylcellulose (NATROSOL M ™) 0.50 Sodium metabisulfite 0.10Sodium chloride (0.9%) q.s. Total = 100.0

[0301] Any of the other compounds having a structure according toFormula (I) are used with substantially similar results.

[0302] A human male subject weighing 90 kg (198 lbs), suffering fromcorneal ulcerations, is treated by a method of this invention.Specifically, for 2 months, a saline solution containing 10 mg ofExample 5 is administered to said subject's affected eye twice-daily.

Example G

[0303] A composition for parenteral administration is made comprising:Component Amount Example 2b. 100 mg/ml carrier Carrier: sodium citratebuffer with (percent by weight of carrier): lecithin 0.48%carboxymethylcellulose 0.53 povidone 0.50 methyl paraben 0.11 propylparaben 0.011

[0304] The above ingredients are mixed, forming a suspension.Approximately 2.0 ml of the suspension is administered, via injection,to a human subject with a premetastatic tumor. The injection sitejuxtaposes the tumor. This dosage is repeated twice daily, forapproximately 30 days. After 30 days, symptoms of the disease subside,and dosage is gradually decreased to maintain the patient.

[0305] Other compounds having a structure according to Formula I areused with substantially similar results.

Example H

[0306] A mouthwash composition is prepared; Component % w/v Example 2c.3.00 SDA 40 Alcohol 8.00 Flavor 0.08 Emulsifier 0.08 Sodium Fluoride0.05 Glycerin 10.00 Sweetener 0.02 Benzoic acid 0.05 Sodium hydroxide0.20 Dye 0.04 Water balance to 100%

[0307] A patient with gum disease uses 1 ml of the mouthwash thricedaily to prevent further oral degeneration.

[0308] Other compounds having a structure according to Formula I areused with substantially similar results.

Example I

[0309] A lozenge composition is prepared; Component % w/v Example 2a.0.01 Sorbitol 17.50 Mannitol 17.50 Starch 13.60 Sweetener 1.20 Flavor11.70 Color 0.10 Corn Syrup balance to 100%

[0310] A patient uses the losenge to prevent loosening of an implant inthe maxilla. Other compounds having a structure according to Formula Iare used with substantially similar results.

Example J Chewing Gum Composition

[0311] Component w/v % Example 1 0.03 Sorbitol crystals 38.44 Paloja-Tgum base* 20.00 Sorbitol (70% aqueous solution) 22.00 Mannitol 10.00Glycerine 7.56 Flavor 1.00

[0312] A patient chews the gum to prevent loosening to prevent looseningof dentures.

[0313] Other compounds having a structure according to Formula I areused with substantially similar results.

Example K

[0314] Components w/v % USP Water 54.656 Methylparaben 0.05Propylparaben 0.01 Xanthan Gum 0.12 Guar Gum 0.09 Calcium carbonate12.38 Antifoam 1.27 Sucrose 15.0 Sorbitol 11.0 Glycerin 5.0 BenzylAlcohol 0.2 Citric Acid 0.15 Coolant 0.00888 Flavor 0.0645 Colorant0.0014

[0315] Example 1 is prepared by first mixing 80 kg of gylcerin and allof the benzyl alcohol and heating to 65 C., then slowly adding andmixing together methylparaben, propylparaben, water, xanthan gum, andguar gum. Mix these ingredients for about 12 minutes with a Silversonin-line mixer. Then slowly add in the following ingredients in thefollowing order: remaining glycerin, sorbitol, antifoam C, calciumcarbonate, citric acid, and sucrose. Separately combine flavors andcoolants and then slowly add to the other ingredients. Mix for about 40minutes.

[0316] The patient takes the formulation to prevent flare up of colitis.

[0317] All references described herein are hereby incorporated byreference.

[0318] While particular embodiments of the subject invention have beendescribed, it will be obvious to those skilled in the art that variouschanges and modifications of the subject invention can be made withoutdeparting from the spirit and scope of the invention. It is intended tocover, in the appended claims, all such modifications that are withinthe scope of this invention.

What is claimed is:
 1. A compound having a structure according toFormula (I)

wherein R₁ is H; R₂ is hydrogen, alkyl or acyl; Ar is COR₃ or SO₂R₄; andR₃ is alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl,heteroalkyl, amino, alkylamino, dialkylamino, arylamino andalkylarylamino; R₄ is alkyl, heteroalkyl, aryl, or heteroaryl,substituted or unsubstituted; X is CH₂, O, S, SO, SO₂, or NR₅, whereinR₅ is independently chosen from hydrogen, alkyl, heteroalkyl,heteroaryl, aryl, SO₂R₆, COR₇, CSR₈, PO(R₉)₂ or may optionally form aring with W; and R₆ is alkyl, aryl, heteroaryl, heteroalkyl, amino,alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino; R₇is hydrogen, alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl,heteroalkyl, amino, alkylamino, dialkylamino, arylamino andalkylarylamino; R₈ is alkyl, aryl, heteroaryl, heteroalkyl, amino,alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino; R₉is alkyl, aryl, heteroaryl, heteroalkyl; W is hydrogen or one or morelower alkyl moieties, or is an alkylene, arylene, or heteroarylenebridge between two adjacent or nonadjacent carbons (thus forming a fusedring); Y is independently one or more of hydrogen, hydroxy, SR₁₀, SOR₄,SO₂R₄, alkoxy, amino, wherein amino is of formula NR₁₁,R₁₂, wherein R₁₁and R₁₂ are independently chosen from hydrogen, alkyl, heteroalkyl,heteroaryl, aryl, SO₂R₆, COR₇, CSR₈, PO(R₉)₂; and R₁₀ is hydrogen,alkyl, aryl, heteroaryl; Z is nil, a spiro moiety or an oxo groupsubstituted on the heterocyclic ring; n is 1-3. This structure alsoincludes an optical isomer, diastereomer or enantiomer for Formula (I),or a pharmaceutically-acceptable salt, or biohydrolyzable amide, ester,or imide thereof.
 2. The compound of claim 1, wherein X is O, S, SO,SO₂, or NR₅, wherein R₅ is independently chosen from hydrogen, alkyl,heteroalkyl, heteroaryl, aryl, SO₂R₇, COR₈, CSR₉.
 3. The compound ofclaim 1, wherein Ar is SO₂R₄ and R₄ is alkyl, heteroalkyl, aryl, orheteroaryl, substituted or unsubstituted.
 4. The compound of claim 1,wherein Ar is phenyl or substituted phenyl.
 5. The compound of claim 4,wherein Ar is substituted phenyl and the substitution is with hydroxy,alkoxy, nitro or halo.
 6. The compound of claim 5, wherein Ar issubstituted with methoxy, bromo, nitro and butoxy.
 7. The compound ofclaim 6, wherein Ar is substituted at the ortho or para positionrelative to the sulfonyl.
 8. The compound of claim 1, wherein W is oneor more of hydrogen or C₁ to C₄ alkyl.
 9. The compound of claim 1,wherein W is geminal C₁ to C₄ alkyl.
 10. The compound of claim 1 whereinZ is an oxo moiety substituted on the heterocyclic ring.
 11. Apharmaceutical composition comprising: (a) a safe and effective amountof a compound of claim 1; and (b) a pharmaceutically-acceptable carrier.12. A pharmaceutical composition comprising: (a) a safe and effectiveamount of a compound of claim 4; and (b) a pharmaceutically-acceptablecarrier.
 13. A pharmaceutical composition comprising: (a) a safe andeffective amount of a compound of claim 5; and (b) apharmaceutically-acceptable carrier.
 14. A pharmaceutical compositioncomprising: (a) a safe and effective amount of a compound of claim 9;and (b) a pharmaceutically-acceptable carrier.
 15. A pharmaceuticalcomposition comprising: (a) a safe and effective amount of a compound ofclaim 10; and (b) a pharmaceutically-acceptable carrier.
 16. A methodfor preventing or treating a disease associated with unwantedmetalloprotease activity in a mammalian subject, the method comprisingadministering to said subject a safe and effective amount of a compoundof claim
 1. 17. A method for preventing or treating a disease associatedwith unwanted metalloprotease activity in a mammalian subject, themethod comprising administering to said subject a safe and effectiveamount of a compound of claim
 4. 18. A method for preventing or treatinga disease associated with unwanted metalloprotease activity in a humanor other animal subject, the method comprising administering to saidsubject a safe and effective amount of a compound of claim
 5. 19. Amethod for preventing or treating a disease associated with unwantedmetalloprotease activity in a mammalian subject, the method comprisingadministering to said subject a safe and effective amount of a compoundof claim
 9. 20. A method for preventing or treating a disorder modulatedby metalloproteases, wherein the disorder is chosen from the groupcomprising, arthritis, cancer, cardiovascular disorders, skin disorders,ocular disorders, inflammation and gum disease by administering to amammal in need of such treatment, a safe and effective amount of ametalloprotease inhibitor according to claim
 1. 21. A method forpreventing or treating a disorder according to claim 20, wherein thedisorder is arthritis, and is chosen from the group comprising,osteoarthritis and rheumatoid arthritis.
 22. A method for preventing ortreating a disorder according to claim 20, wherein the disorder iscancer, and the treatment prevents or arrests tumor growth andmetastasis.
 23. A method for the preventing or treating a disorderaccording to claim 20, wherein the disorder is a cardiovascular disorderchosen from the group compromising dilated cardiomyopathy, congestiveheart failure, atherosclerosis, plaque rupture, reperfusion injury,ischemia, chronic obstructive pulmonary disease, angioplasty restenosisand aortic aneurysm.
 24. A method for the preventing or treating adisorder according to claim 20, wherein the disorder is an oculardisorder, and is chosen from the group comprising, corneal ulceration,lack of corneal healing, macular degeneration, and pterygium.
 25. Amethod for preventing or treating a disorder according to claim 20,wherein the disorder is gum disease, and is chosen from the groupcomprising, periodontal disease, and gingivitis.
 26. A method forpreventing or treating a condition, according to claim 20, wherein thecondition is skin condition chosen from the group comprising wrinklerepair and prevention, U. V. skin damage, epidermolysis bullosa,psoriasis, sclerodema, atopic dermatitis and scarring.
 27. A method forpreventing the loosening of prosthetic devices chosen from the groupcomprising joint replacements and dental prosthesis by administering toa mammal in need of such treatment, a safe and effective amount of ametalloprotease inhibitor according to claim
 1. 28. A method fortreating inflammatory conditions according to claim 20, chosen from thegroup comprising inflammatory bowel disease, Crohn's Disease, ulcerativecolitis, pancreatitis, diverticulitis, acne inflammation, osteomylitis,bronchitis, arthritis, asthma.
 29. A method of treating multiplesclerosis, comprising administering to a mammal in need of suchtreatment, a safe and effective amount of a metalloprotease inhibitoraccording to claim
 1. 30. A method for treating musculoskeletal diseaseor cachexia comprising administering to a mammal in need of suchtreatment, a safe and effective amount of a metalloprotease inhibitoraccording to claim 1.